Integrated circuit with improved charge transfer efficiency and associated techniques

ABSTRACT

The present disclosure provides techniques for improving the rate and efficiency of charge transfer within an integrated circuit configured to receive incident photons. Some aspects of the present disclosure relate to integrated circuits that are configured to induce one or more intrinsic electric fields that increase the rate and efficiency of charge transfer within the integrated circuits. Some aspects of the present disclosure relate to integrated circuits configured to induce a charge carrier depletion in the photodetection region(s) of the integrated circuits. In some embodiments, the charge carrier depletion in the photodetection region(s) may be intrinsic, in that the depletion is induced even in the absence of external electric fields applied to the integrated circuit. Some aspects of the present disclosure relate to processes for operating and/or manufacturing integrated devices as described herein.

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application Ser. No. 63/124,655, filed Dec. 11, 2020, underAttorney Docket No.: R0708.70111US00, and titled, “INTEGRATED CIRCUITWITH IMPROVED CHARGE TRANSFER EFFICIENCY AND ASSOCIATED TECHNIQUES,”which is herein incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to integrated devices and relatedinstruments that can perform massively-parallel analyses of samples byproviding short optical pulses to tens of thousands of sample wells ormore simultaneously and receiving fluorescent signals from the samplewells for sample analyses. The instruments may be useful forpoint-of-care genetic sequencing and for personalized medicine.

BACKGROUND

Photodetectors are used to detect light in a variety of applications.Integrated photodetectors have been developed that produce an electricalsignal indicative of the intensity of incident light. Integratedphotodetectors for imaging applications include an array of pixels todetect the intensity of light received from across a scene. Examples ofintegrated photodetectors include charge coupled devices (CCDs) andComplementary Metal Oxide Semiconductor (CMOS) image sensors.

Instruments that are capable of massively-parallel analyses ofbiological or chemical samples are typically limited to laboratorysettings because of several factors that can include their large size,lack of portability, requirement of a skilled technician to operate theinstrument, power need, need for a controlled operating environment, andcost. When a sample is to be analyzed using such equipment, a commonparadigm is to extract a sample at a point of care or in the field, sendthe sample to the lab and wait for results of the analysis. The waittime for results can range from hours to days.

SUMMARY OF THE DISCLOSURE

Some aspects of the present disclosure provide an integrated circuitcomprising a photodetection region configured to receive, in a firstdirection, incident photons, generate, in response to receiving theincident photons, charge carriers, and induce, in the first direction, afirst intrinsic electric field and one or more charge storage regionsconfigured to receive the charge carriers from the photodetectionregion.

Some aspects of the present disclosure provide a method comprisinginducing, in a first direction, a first intrinsic electric field in aphotodetection region of an integrated circuit, receiving, in the firstdirection, incident photons at the photodetection region, and receiving,at one or more charge storage regions of the integrated circuit, chargecarriers generated in the photodetection region in response to theincident photons.

Some aspects of the present disclosure provide an integrated circuitcomprising a photodetection region configured to generate, in responseto receiving incident photons, charge carriers and induce, in a firstdirection, a first intrinsic electric field, one or more charge storageregions configured to receive the charge carriers from thephotodetection region, and one or more transfer gates positioned, in thefirst direction, after the photodetection region and the one or morecharge storage regions, and configured to control transfer of chargecarriers from the photodetection region to the one or more chargestorage regions and/or from the one or more charge storage regions to areadout region.

Some aspects of the present disclosure provide a method comprisinginducing, in a first direction, a first intrinsic electric field in aphotodetection region of an integrated circuit, generating, in thephotodetection region in response to receiving incident photons, chargecarriers, receiving, at one or more charge storage regions, the chargecarriers from the photodetection region, and controlling transfer ofcharge carriers from the photodetection region to the one or more chargestorage regions and/or from the one or more charge storage regions to areadout region using one or more transfer gates positioned, in the firstdirection, after the photodetection region and the one or more chargestorage regions.

Some aspects of the present disclosure provide an integrated circuitcomprising a photodetection region configured to receive, in a firstdirection, incident photons and generate, in response to receiving theincident photons, charge carriers, one or more charge storage regionsconfigured to receive the charge carriers from the photodetectionregion, and one or more charged and/or biased regions configured toinduce a charge carrier depletion in the photodetection region forpropagating the charge carriers, at least partially in the firstdirection, from the photodetection region toward the one or more chargestorage regions.

Some aspects of the present disclosure provide a method comprisinginducing in a photodetection region of an integrated circuit, a chargecarrier depletion, receiving, in a first direction, incident photons atthe photodetection region, generating, in the photodetection region inresponse to receiving the incident photons, charge carriers,propagating, at least partially in the first direction, and receiving,at one or more charge storage regions of the integrated circuit, thecharge carriers from the photodetection region.

Some aspects of the present disclosure provide an integrated circuitcomprising a photodetection region configured to receive, in a firstdirection, incident photons and generate, in response to receiving theincident photons, charge carriers, one or more charge storage regionsconfigured to receive the charge carriers from the photodetectionregion, and one or more regions configured to induce an intrinsic chargecarrier depletion in the photodetection region.

Some aspects of the present disclosure provide a method comprisinginducing in a photodetection region of an integrated circuit, anintrinsic charge carrier depletion, receiving, in a first direction,incident photons at the photodetection region, generating, in thephotodetection region in response to receiving the incident photons,charge carriers and receiving, at one or more charge storage regions ofthe integrated circuit, the charge carriers from the photodetectionregion.

Some aspects of the present disclosure provide a method of manufacturingan integrated circuit, the method comprising forming a photodetectionregion of the integrated circuit so as to induce, in the photodetectionregion in a first direction in which the photodetection region isconfigured to receive incident photons, a first electric field.

Some aspects of the present disclosure provide a method of manufacturingan integrated circuit, the method comprising forming a photodetectionregion of the integrated circuit and forming one or more charged regionsto induce an intrinsic charge carrier depletion in the photodetectionregion.

Some aspects of the present disclosure provide a method of manufacturingan integrated circuit, the method comprising forming one or more chargedand/or biased regions between a first photodetection region of a firstpixel and a second photodetection region of a second pixel.

The foregoing summary is not intended to be limiting. Moreover, inaccordance with various embodiments, aspects of the present disclosuremay be implemented alone or in combination with other aspects.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1-1 is a cross-sectional schematic of an exemplary integrateddevice illustrating a row of pixels, according to some embodiments.

FIG. 1-2 is a cross-sectional view of a pixel of the integrated deviceof FIG. 1-1, according to some embodiments.

FIG. 1-3 is a circuit diagram of the pixel of FIG. 1-2, according tosome embodiments.

FIG. 1-4 is a diagram showing example charge transfer in the pixel ofFIG. 1-3, according to some embodiments.

FIG. 2-1A is a top view of an example array of pixels with shieldportions that may be included in the integrated device of FIG. 1-1,according to some embodiments.

FIG. 2-1B is a top view of an example array of pixels that may beincluded in the integrated device of FIG. 1-1 including shield portionsin an alternative configuration, according to some embodiments.

FIG. 2-1C is a top view of an example array of pixels that may beincluded in the integrated device of FIG. 1-1 including shield portionsin a further alternative configuration, according to some embodiments.

FIG. 2-2A is a top view of a pixel of the array shown in FIG. 2-1A,according to some embodiments.

FIG. 2-2B is a top view of a pixel of the array shown in FIG. 2-1B,according to some embodiments.

FIG. 2-2C is a top view of a pixel of the array shown in FIG. 2-1C,according to some embodiments.

FIG. 2-3 is a layout sketch of an example pixel that may be included inthe arrays of FIGS. 2-1A, 2-1B, or 2-1C, according to some embodiments.

FIG. 2-4A is a layout sketch of an alternative example pixel that may beincluded in the arrays of FIGS. 2-1A, 2-1B, and 2-1C, according to someembodiments.

FIG. 2-4B is a layout sketch of the pixel of FIG. 2-4A, according tosome embodiments.

FIG. 2-5A is a layout sketch of an example pixel having discontinuousC/B regions that may be included in the arrays of FIGS. 2-1A, 2-1B, and2-1C, according to some embodiments.

FIG. 2-5B is a layout sketch of an alternative example pixel havingdiscontinuous C/B regions that may be included in the arrays of FIGS.2-1A, 2-1B, and 2-1C, according to some embodiments.

FIG. 2-6A is a cross-sectional schematic view of an example pixel thatmay be included in the arrays of FIGS. 2-1A and 2-1B, according to someembodiments.

FIG. 2-6B is a cross-sectional schematic view of an alternative examplepixel that may be included in the arrays of FIGS. 2-1A and 2-1Baccording to some embodiments.

FIG. 2-7A is a cross-sectional schematic view of an example pixel thatmay be included in the arrays of FIGS. 2-1A and 2-1B with aphotodetection region extending below the charge storage regions,according to some embodiments.

FIG. 2-7B is a cross-sectional schematic of a view of an alternativeexample pixel that may be included in the arrays of FIG. 2-1A and 2-1Bwith a photodetection region extending below the charge storage regions,according to some embodiments.

FIG. 2-8 is a cross-sectional schematic view of an example pixel thatmay be included in the arrays of FIGS. 2-1A and 2-1B with barriersextending alongside only a portion of the photodetection region in thefirst direction, according to some embodiments.

FIG. 2-9 is a cross-sectional schematic view of the pixel of FIG. 2-2C,according to some embodiments.

FIG. 2-10 is a cross-sectional schematic view of an example pixel thatmay be included in the array of FIG. 2-1C having charged and/or biasedregions extending alongside the photodetection region from the shieldsto the transfer gates in the first direction, according to someembodiments.

FIG. 2-11 is a cross-sectional schematic view of an example pixel thatmay be included in the array of FIG. 2-1C having multiple barrierspositioned alongside the photodetection region in the first direction,according to some embodiments.

FIG. 2-12 is a cross-sectional schematic view of a portion of an examplepixel that may be included in the arrays of FIGS. 2-1A, 2-1B, and 2-1C,according to some embodiments.

FIG. 2-13 is a layout sketch of an example pixel having multiple chargestorage regions that may be included in the arrays of FIGS. 2-1A, 2-1B,and 2-1C, according to some embodiments.

FIG. 2-14 is a diagram showing example charge transfer in the pixel ofFIG. 2-13, according to some embodiments.

FIG. 3-1 is a perspective view of an example pixel that may be includedin the integrated device of FIG. 1-1 showing dopant concentration withinthe pixel, according to some embodiments.

FIG. 3-2 is a side view of a cross-section of the pixel of FIG. 3-1showing dopant concentration within the pixel, according to someembodiments.

FIG. 3-3 is a graph of n-type and total dopant concentration versusdepth in a first sub-cross-section of the pixel of FIG. 3-2, accordingto some embodiments.

FIG. 3-4 is a graph of p-type dopant concentration versus depth in asecond sub-cross-section of the pixel of FIG. 3-2, according to someembodiments.

FIG. 3-5A is a side view of a cross-section of the pixel of FIG. 3-1incorporating techniques described herein showing charge carrier densitywithin the pixel, according to some embodiments.

FIG. 3-5B is a side view of a cross-section of another example pixelshowing charge carrier density within the pixel, according to someembodiments.

FIG. 3-6A is a graph showing a number of charge carriers at differentdepths of the pixels of FIGS. 3-5A and 3-5B over time, according to someembodiments.

FIG. 3-6B is a magnified view of a portion of the graph of FIG. 3-6A,according to some embodiments.

FIG. 3-7A is a side view of a cross-section of the pixel of FIG. 3-1incorporating techniques described herein showing electric fields withinthe pixel, according to some embodiments.

FIG. 3-7B is a side view of a cross-section of the pixel of FIG. 3-5Bshowing electric fields within the pixel, according to some embodiments.

FIG. 3-8 is a graph of electric field versus depth forsub-cross-sections of the pixels of FIGS. 3-1 and 3-5B, according tosome embodiments.

FIG. 3-9A is a graph showing a number of charge carriers at differentdepths of the pixel of FIG. 3-1 over time, according to someembodiments.

FIG. 3-9B is a magnified view of a portion of the graph of FIG. 3-9A,according to some embodiments.

FIG. 3-9C is a further magnified view of a portion of the graph of FIG.3-9B, according to some embodiments.

FIG. 3-10 is a graph showing a number of charge carriers over time formultiple pixels having different configurations, according to someembodiments.

FIG. 3-11A is a side view of a cross-section of the pixel of FIG. 3-1showing charge carrier density within the pixel 1 nanosecond after anexcitation pulse, according to some embodiments.

FIG. 3-11B is a side view of a cross-section of another example pixelshowing charge carrier density within the pixel 1 nanosecond after anexcitation pulse, according to some embodiments.

FIG. 3-12A is a side view of a cross-section of the pixel of FIG. 3-1showing electric fields within the pixel, according to some embodiments.

FIG. 3-12B is a side view of a cross-section of the pixel of FIG. 3-11Bshowing electric fields within the pixel, according to some embodiments.

FIG. 3-13 is a graph of electric field versus depth forsub-cross-sections of the pixels of FIGS. 3-1 and 3-11B, according tosome embodiments.

FIG. 4-1 is a side view of a cross-section of an example pixel with oneor more charged regions that may be included in the integrated device ofFIG. 1-1, according to some embodiments.

FIG. 4-2 is a side view of a cross-section of an example pixel with oneor more metal regions that may be included in the integrated device ofFIG. 1-1, according to some embodiments.

FIG. 4-3 is a side view of a cross-section of an example pixel with oneor more charged regions and an optically directive structure that may beincluded in the integrated device of FIG. 1-1, according to someembodiments.

FIG. 5-1A is a block diagram of an integrated device and an instrument,according to some embodiments.

FIG. 5-1B is a schematic of an apparatus including an integrated device,according to some embodiments.

FIG. 5-1C is a block diagram depiction of an analytical instrument thatincludes a compact mode-locked laser module, according to someembodiments.

FIG. 5-1D depicts a compact mode-locked laser module incorporated intoan analytical instrument, according to some embodiments.

FIG. 5-2 depicts a train of optical pulses, according to someembodiments.

FIG. 5-3 depicts an example of parallel reaction chambers that can beexcited optically by a pulsed laser via one or more waveguides accordingto some embodiments.

FIG. 5-4 illustrates optical excitation of a reaction chamber from awaveguide, according to some embodiments.

FIG. 5-5 depicts further details of an integrated reaction chamber,optical waveguide, and time-binning photodetector, according to someembodiments.

FIG. 5-6 depicts an example of a biological reaction that can occurwithin a reaction chamber, according to some embodiments.

FIG. 5-7 depicts emission probability curves for two differentfluorophores having different decay characteristics according to someembodiments.

FIG. 5-8 depicts time-binning detection of fluorescent emission,according to some embodiments.

FIG. 5-9 depicts a time-binning photodetector, according to someembodiments.

FIG. 5-10A depicts pulsed excitation and time-binned detection offluorescent emission from a sample, according to some embodiments.

FIG. 5-10B depicts a histogram of accumulated fluorescent photon countsin various time bins after repeated pulsed excitation of a sample,according to some embodiments.

FIG. 5-11A depicts a histogram corresponding to a T nucleotide ornucleotide analog, according to some embodiments.

FIG. 5-11B depicts a histogram corresponding to an A nucleotide ornucleotide analog, according to some embodiments.

FIG. 5-11C depicts a histogram corresponding to a C nucleotide ornucleotide analog, according to some embodiments.

FIG. 5-11D depicts a histogram corresponding to a G nucleotide ornucleotide analog, according to some embodiments.

FIG. 5-12 is a flow diagram illustrating a method of sequencing alabeled polypeptide by Edman degradation according to some embodiments.

FIG. 5-13 includes a flow diagram illustrating a method of sequencing inwhich discrete binding events give rise to signal pulses of a signaloutput, and a graph illustrating the signal output according to someembodiments.

The features and advantages of the present disclosure will become moreapparent from the detailed description set forth below when taken inconjunction with the drawings. When describing embodiments in referenceto the drawings, directional references (“above,” “below,” “top,”“bottom,” “left,” “right,” “horizontal,” “vertical,” etc.) may be used.Such references are intended merely as an aid to the reader viewing thedrawings in a normal orientation. These directional references are notintended to describe a preferred or only orientation of features of anembodied device. A device may be embodied using other orientations.

DETAILED DESCRIPTION

I. Introduction

Aspects of the present disclosure relate to integrated devices,instruments and related systems capable of analyzing samples inparallel, including identification of single molecules and nucleic acidsequencing. Such an instrument may be compact, easy to carry, and easyto operate, allowing a physician or other provider to readily use theinstrument and transport the instrument to a desired location where caremay be needed. Analysis of a sample may include labeling the sample withone or more fluorescent markers, which may be used to detect the sampleand/or identify single molecules of the sample (e.g., individualnucleotide identification as part of nucleic acid sequencing). Afluorescent marker may become excited in response to illuminating thefluorescent marker with excitation light (e.g., light having acharacteristic wavelength that may excite the fluorescent marker to anexcited state) and, if the fluorescent marker becomes excited, emitemission light (e.g., light having a characteristic wavelength emittedby the fluorescent marker by returning to a ground state from an excitedstate). Detection of the emission light may allow for identification ofthe fluorescent marker, and thus, the sample or a molecule of the samplelabeled by the fluorescent marker. According to some embodiments, theinstrument may be capable of massively-parallel sample analyses and maybe configured to handle tens of thousands of samples or moresimultaneously.

The inventors have recognized and appreciated that an integrated devicehaving sample wells configured to receive the sample and integratedoptics formed on the integrated device and an instrument configured tointerface with the integrated device may be used to achieve analysis ofthis number of samples. The instrument may include one or moreexcitation light sources, and the integrated device may interface withthe instrument such that the excitation light is delivered to the samplewells using integrated optical components (e.g., waveguides, opticalcouplers, optical splitters) formed on the integrated device. Theoptical components may improve the uniformity of illumination across thesample wells of the integrated device and may reduce a large number ofexternal optical components that might otherwise be needed. Furthermore,the inventors have recognized and appreciated that integratingphotodetection regions (e.g., photodiodes) on the integrated device mayimprove detection efficiency of fluorescent emissions from the samplewells and reduce the number of light-collection components that mightotherwise be needed.

In some embodiments, the integrated device may receive fluorescenceemission photons and transmit charge carriers to one or more chargestorage regions. For example, a photodetection region may be positionedon the integrated device to receive the fluorescent emission photons inan optical direction, and the photodetection region also may be coupledto one or more charge storage regions (e.g., storage diodes) of theintegrated device, such that the charge storage region(s) may collectcharge carriers generated in the photodetection region in response tothe fluorescent emission photons. A number of charge carriersaccumulated in the charge storage region(s) may be read out to obtaininformation about the sample from which the fluorescence emissionphotons were received.

The inventors have recognized that it is desirable to generate andtransfer charge carriers from the photodetection region to the chargestorage region(s) as quickly and efficiently as possible, but that it ischallenging to do so quickly and efficiently when the charge storageregion(s) are positioned far from where incident photons are received atthe integrated device. For instance, it can take a long time for chargecarriers generated in the integrated device in response to the incidentphotons to reach the charge storage region(s). The long travel time cancause charge carriers to reach the charge storage region(s) at a timethat is too late to be useful, as the arrival times of the chargecarriers may be used to obtain information about the sample. In suchcases, a large quantity of late arriving charge carriers can indicatefalse timing information about the sample, causing inaccurateinformation to be extracted from the integrated device. Quick andefficient charge transfer is particularly challenging in integrateddevices in which the integrated device receives the incident photons onone side of the integrated device and the charge storage region(s)and/or transfer gate(s) are on an opposite side of the integrateddevice.

To solve the above problems, the inventors have developed integrateddevices and associated techniques that increase the rate and efficiencyof charge carrier generation and transfer within the integrated devices.Some aspects of the present disclosure relate to integrated circuitsthat are configured to induce one or more intrinsic electric fields thatincrease the rate and efficiency of charge transfer within theintegrated circuits. Electric fields are intrinsically induced when theyare present even in the absence of any electric fields appliedexternally to the integrated circuit.

In some embodiments, an integrated circuit may have a photodetectionregion and one or more charge storage regions. The photodetection regionmay be configured to receive, in a first direction (e.g., a directionfrom the sample well towards the photodetection region), incidentphotons and induce, in the first direction, a first intrinsic electricfield. For example, the photodetection region may have multiple layerspositioned one after another in the first direction and each havingdifferent intrinsic electric potential levels, such as having differentdopant concentrations. In this example, the first electric field may beinduced intrinsically in that the layers of the photodetection regionmay be configured to induce the electric field even when no externalelectric fields are applied to the integrated circuit. The chargestorage region(s) may be configured to receive charge carriers generatedin the photodetection region in response to incident photons. Byinducing the first intrinsic electric field in the first direction,charge carriers generated in the photodetection region can betransferred quickly and efficiently by the first intrinsic electricfield in the first direction toward the charge storage region(s).

In accordance with various embodiments, intrinsic electric fieldsdescribed herein may be induced in any direction, and/or in multipledirections, as appropriate for transferring charge carriers within anintegrated device. For example, integrated devices described herein maybe configured to induce intrinsic electric fields in first and secondperpendicular directions where charge carriers are to be transferred inthe first direction within the photodetection region and in the seconddirection from the photodetection region to the charge storageregion(s). In some embodiments, intrinsic electric fields describedherein may be supplemented with externally applied electric fields. Forexample, intrinsic electric fields may allow for externally appliedelectric fields of smaller magnitude to be applied to the integrateddevice, thereby reducing power consumption and/or heat dissipation inthe integrated device.

In some embodiments, an integrated circuit may have a photodetectionregion configured to induce, in a first direction, a first intrinsicelectric field, one or more charge storage regions configured to receivecharge carriers generated in the photodetection region in response toincident photons, and one or more transfer gates positioned, in thefirst direction, after the photodetection region and the charge storageregion(s) and configured to control transfer of charge carriers from thephotodetection region to the charge storage region(s). The transfergates may be positioned, in the first direction, after thephotodetection region and the charge storage region(s) in that incidentphotons or charge carriers traveling along the first direction wouldreach the position(s) of the photodetection region and/or charge storageregion(s) along the first direction before reaching the positions of thetransfer gates along the first direction. For example, the transfergate(s) and charge storage region(s) may be positioned on an oppositeside of the integrated device from the side on which the photodetectionregion is configured to receive incident photons, such that chargecarriers have a long distance to travel to reach the charge storageregion(s). In this example, the first intrinsic electric field mayquickly and efficiently transfer charge carriers to the charge storageregion(s), thereby facilitating positioning the charge storage region(s)and transfer gate(s) on the opposite of the integrated device. Theinventors recognized that this configuration is desirable because fewerincident photons may reach the charge storage region(s) and generatenoise charge carriers therein than if the charge storage region(s), andthe optical characteristics of the transfer gate(s) may have less effecton incident photons, than if the charge storage region(s) and transfergate(s) were positioned on the side of the integrated device thatreceives incident photons.

Some aspects of the present disclosure relate to integrated circuitsconfigured to induce a charge carrier depletion in the photodetectionregion(s) of the integrated circuits. The inventors have recognized thatthe presence of free charge carriers in the photodetection region canaffect the rate and efficiency of charge transfer within thephotodetection region and between the photodetection region and thecharge storage region(s). In some embodiments, an integrated circuit mayinclude a photodetection region configured to receive, in a firstdirection, incident photons, and generate, in response to receiving theincident photons, charge carriers and one or more charge storage regionsconfigured to receive the charge carriers from the photodetectionregion. The integrated circuit may further include one or more chargedand/or biased regions configured to induce a charge carrier depletion inthe photodetection region for propagating the charge carriers, at leastpartially in the first direction, from the photodetection region towardthe charge storage region(s). For example, the charged and/or biasedregions may include a charge layer configured to deplete thephotodetection region of charge carriers by attracting the chargecarriers to the charge layer. In this example, the charge layer may beconfigured to induce an intrinsic charge carrier depletion in thephotodetection region, in that the charge layer may deplete thephotodetection region even when no external electric field or otherexternal means of depletion is applied to the integrated device.

Alternatively or additionally, the charged and/or biased region mayinclude a metal region configured to receive a voltage bias that inducesthe charge carrier depletion in the photodetection region. For example,the voltage bias may be supplied to the integrated device from anexternal power source, such as a ground connection to a power supply. Byinducing a charge carrier depletion in the photodetection region, thephotodetection region may receive generate and transfer charge carriersmore quickly and efficiently in response to incident photons. In someembodiments, the photodetection region may have fewer than 10¹² chargecarriers per cubic centimeter (cm³), fewer than 10⁶ charge carriers percm³, and/or fewer than 10³ charge carriers per cm³ when thephotodetection region is depleted of charge carriers.

The inventors have also developed processes for operating and/ormanufacturing integrated devices as described herein. It should beappreciated that techniques described herein may be implemented alone orin combination, as the present disclosure is not so limited.

II. Integrated Device Overview

A cross-sectional schematic of integrated device 1-102 illustrating arow of pixels 1-112 is shown in FIG. 1-1, according to some embodiments.Integrated device 1-102 may include coupling region 1-201, routingregion 1-202, and pixel region 1-203. Coupling region 1-201 may beconfigured to receive incident excitation light from an excitation lightsource. Routing region 1-202 may be configured to deliver the excitationlight from coupling region 1-201 to pixel region 1-203. Pixel region1-203 may include a plurality of sample wells 1-108 positioned on asurface at a location separate from coupling region 1-201. For example,coupling region 1-201 may include one or more grating couplers 1-216 androuting region 1-202 may include one or more waveguides 1-220 configuredto propagate light from grating coupler(s) 1-216 under sample well(s)1-108. For instance, evanescent coupling of excitation light fromwaveguide(s) 1-220 may excite samples in sample well(s) 1-108 to emitfluorescent light.

As shown in FIG. 1-1, one or more at least partially opaque (e.g.,metal) layers 1-106 can be disposed over the surface to reflect incidentexcitation light coupled from waveguide(s) 1-220. Sample wells 1-108 maybe free of layer(s) 1-106 to allow samples to be placed in samplewell(s) 1-108. In some embodiments, the directionality of the emissionlight from a sample well 1-108 may depend on the positioning of thesample in the sample well 1-108 relative to metal layer(s) 1-106 becausemetal layer(s) 1-106 may act to reflect emission light. In this manner,a distance between metal layer(s) 1-106 and a fluorescent marker on asample positioned in a sample well 1-108 may impact the efficiency ofphotodetector(s) 1-110, that are in the same pixel as the sample well,to detect the light emitted by the fluorescent marker. The distancebetween metal layer(s) 1-106 and the bottom surface of a sample well1-108, which is proximate to where a sample may be positioned duringoperation, may be in the range of 100 nm to 500 nm, or any value orrange of values in that range. In some embodiments the distance betweenmetal layer(s) 1-106 and the bottom surface of a sample well 1-108 isapproximately 300 nm.

As shown in FIG. 1-1, pixel region 1-203 can include one or more rows ofpixels 1-112. One pixel 1-112, illustrated by the dotted rectangle, is aregion of integrated device 1-102 that includes a sample well 1-108 andone or more photodetectors 1-110 (e.g., including a photodetectionregion) associated with the sample well 1-108. In some embodiments, eachphotodetector 1-110 can include a photodetection region and one or morecharge storage regions configured to receive charge carriers generatedin the photodetection region in response to incident light from thesample well 1-108. When excitation light coupled from waveguide(s) 1-220illuminates a sample located within the sample well 1-108, the samplemay reach an excited state and emit emission light. The emission lightmay be detected by one or more photodetectors 1-110 associated with thesample well 1-108. FIG. 1-1 schematically illustrates an optical axis ofemission light (shown as the solid line) from a sample well 1-108 tophotodetector(s) 1-110 of pixel 1-112. The photodetector(s) 1-110 ofpixel 1-112 may be configured and positioned to detect emission lightfrom sample well 1-108. For an individual pixel 1-112, a sample well1-108 and its respective photodetector(s) 1-110 may be aligned along acommon optical axis. In this manner, the photodetector(s) 1-110 mayoverlap with the sample well 1-108 within a pixel 1-112.

Also shown in FIG. 1-1, integrated device 1-102 can include one or morephotonic structures 1-230 positioned between sample wells 1-108 andphotodetectors 1-110. For example, photonic structures 1-230 may beconfigured to increase the amount of emission light that reachesphotodetectors 1-110 from sample wells 1-108. Alternatively oradditionally, photonic structures 1-230 may be configured to reduce orprevent excitation light from reaching photodetectors 1-110, which mayotherwise contribute to signal noise in detecting the emission light. Asshown in FIG. 1-1, photonic structures 1-230 may be positioned betweenwaveguide(s) 1-220 and photodetectors 1-110. According to variousembodiments, photonic structures 1-230 may include one or more opticalrejection photonic structures including a spectral filter, apolarization filter, and a spatial filter. In some embodiments, photonicstructures 1-230 may be positioned to align with individual sample wells1-108 and their respective photodetector(s) 1-110 along a common axis.

As shown in FIG. 1-1, metal layers 1-240 may be positioned on anopposite side of photodetectors 1-110 from the side that faces samplewells 1-108. In some embodiments, metal layers 1-240 may be configuredto route control signals to and/or from portions of integrated device1-102. For example, the control signals may be received from a controlcircuit within and/or coupled to one or more conductive pads (not shown)of integrated device 1-102 and routed to pixels 1-112 via metal layers1-240.

In some embodiments, the distance between the sample and thephotodetector(s) may also impact efficiency in detecting emission light.By decreasing the distance light has to travel between the sample andthe photodetector(s) 1-110, detection efficiency of emission light maybe improved. In addition, smaller distances between the sample and thephotodetector(s) 1-110 may allow for pixels that occupy a smaller areafootprint of the integrated device, which can allow for a higher numberof pixels to be included in the integrated device. At the same time, thesubstrate depth at which photodetectors 1-110 are disposed can affectthe amount of generated charge carriers that flow through to the side onwhich metal layers 1-240 are disposed. The distance between the bottomsurface of a sample well 1-108 and the photodetector(s) 1-110 may be inthe range of 5 μm to 15 μm, or any value or range of values in thatrange, in some embodiments, but embodiments are not so limited. Itshould be appreciated that, in some embodiments, emission light may beprovided through other means than an excitation light source and asample well. Accordingly, some embodiments may not include sample well1-108.

A sample to be analyzed may be introduced into sample well 1-108 ofpixel 1-112. The sample may be a biological sample or any other suitablesample, such as a chemical sample. The sample may include multiplemolecules and the sample well may be configured to isolate a singlemolecule. In some instances, the dimensions of the sample well 1-108 mayact to confine a single molecule within the sample well 1-108, allowingmeasurements to be performed on the single molecule. Excitation lightmay be delivered into the sample well 1-108, so as to excite the sampleor at least one fluorescent marker attached to the sample or otherwiseassociated with the sample while it is within an illumination areawithin the sample well 1-108.

In operation, parallel analyses of samples within the sample wells 1-108are carried out by exciting some or all of the samples within the wellsusing excitation light and detecting signals from sample emission withthe photodetectors 1-110. Emission light from a sample may be detectedby a corresponding photodetector 1-110 and converted to at least oneelectrical signal. The electrical signals may be transmitted alongconducting lines (e.g., metal layers 1-240) of integrated device 1-102,which may be connected to an instrument and/or control circuitinterfaced with the integrated device 1-102. The electrical signals maybe subsequently processed and/or analyzed by the instrument and/orcontrol circuit.

FIG. 1-2 illustrates a cross-sectional view of a pixel 1-112 ofintegrated device 1-102, according to some embodiments. As shown in FIG.1-2, pixel 1-112 includes a photodetection region, which may be a pinnedphotodiode (PPD), a charge storage region, which may be a storage diode(SD0), a readout region, which may be a floating diffusion (FD) region,a drain region D, and transfer gates REJ, ST0, and TX0. In someembodiments, photodetection region PPD, charge storage region SD0,readout region FD, and/or drain region D may be formed in the integrateddevice 1-102 by doping portions of one or more substrate layers of theintegrated device 1-102. For example, the integrated device 1-102 mayhave a lightly p-doped substrate, and photodetection region PPD, chargestorage region SD0, readout region FD, and/or drain region D may ben-doped regions of the substrate. In this example, p-doped regions maybe doped using boron and n-doped regions may be doped using phosphorus,although other dopants and configurations are possible. In someembodiments, pixel 1-112 may have an area smaller than or equal to 10microns by 10 microns, such as smaller than or equal to 7.5 microns×5microns. It should be appreciated that, in some embodiments, thesubstrate may be lightly n-doped and photodetection region PPD, chargestorage region SD0, readout region FD, and/or drain region D may bep-doped, as embodiments described herein are not so limited.

In FIG. 1-2, photodetection region PPD is configured to receive incidentphotons in a first direction Dir1, and charge storage region SD0, drainregion D, and readout region FD are positioned, in the first directionDir1, after at least a portion of photodetection region PPD. Forexample, in FIG. 1-2, portions of photodetection region PPD arepositioned between charge storage region SD0, drain region D, andreadout region FD and sample well 1-108. Transfer gates ST0, TX0, andREJ are shown in FIG. 1-2 positioned, in the first direction Dir1, afterphotodetection region PPD, charge storage region SD0, readout region FD,and drain region D. Pixel 1-112 is also shown in FIG. 1-2 including oneor more charged and/or biased (C/B) regions, which are described furtherherein including with reference to FIGS. 2-1A to 2-13.

In some embodiments, photodetection region PPD may be configured togenerate charge carriers in response to incident light. For instance,during operation of pixel 1-112, excitation light may illuminate samplewell 1-108 causing incident photons, including fluorescent emissionsfrom a sample, to flow along the optical axis OPT to photodetectionregion PPD, which may be configured to generate fluorescent emissioncharge carriers in response to the incident photons from sample well1-108. In some embodiments, the integrated device 1-102 may beconfigured to transfer the charge carriers to drain region D or tocharge storage region SD0. For example, during a drain period followinga pulse of excitation light, the incident photons reachingphotodetection region PPD may be predominantly excitation photons to betransferred to drain region D to be discarded. In this example, during acollection period following the drain period, fluorescent emissionphotons may reach photodetection region PPD to be transferred to chargestorage region SD0 for collection. In some embodiments, a drain periodand collection period may follow each excitation pulse.

In some embodiments, charge storage region SD0 may be configured toreceive charge carriers generated in photodetection region PPD inresponse to the incident light. For example, charge storage region SD0may be configured to receive and store charge carriers generated inphotodetection region PPD in response to fluorescent emission photonsfrom the sample well 1-108. In some embodiments, charge storage regionSD0 may be configured to accumulate charge carriers received fromphotodetection region PPD over the course of multiple collectionperiods, each preceded by an excitation pulse. In some embodiments,charge storage region SD0 may be electrically coupled to photodetectionregion PPD by a charge transfer channel. In some embodiments, the chargetransfer channel may be formed by doping a region of pixel 1-112 betweenphotodetection region PPD and charge storage region SD0 with a sameconductivity type as photodetection region PPD and charge storage regionSD0 such that the charge transfer channel is configured to be conductivewhen at least a threshold voltage is applied to the charge transferchannel and nonconductive when a voltage less than (or greater than, forsome embodiments) the threshold voltage is applied to the chargetransfer channel. In some embodiments, the threshold voltage may be avoltage above (or below) which the charge transfer channel is depletedof charge carriers, such that charge carriers from photodetection regionPPD may travel through the charge transfer channel to charge storageregion SD0. For example, the threshold voltage may be determined basedon the materials, dimensions, and/or doping configuration of the chargetransfer channel.

In some embodiments, transfer gate ST0 may be configured to controltransfer of charge carriers from photodetection region PPD to chargestorage region SD0. For instance, transfer gate ST0 may be configured toreceive a control signal and responsively determine a conductivity of acharge transfer channel electrically coupling photodetection region PPDto charge storage region SD0. For example, when a first portion of acontrol signal is received at transfer gate ST0, transfer gate ST0 maybe configured to bias the charge transfer channel to cause the chargetransfer channel to be nonconductive, such that charge carriers areblocked from reaching charge storage region SD0. Alternatively, when asecond portion of the control signal is received at transfer gate ST0,transfer gate ST0 may be configured to bias to the charge transferchannel to cause the charge transfer channel to be conductive, such thatcharge carriers may flow from photodetection region PPD to chargestorage region SD0 via the charge transfer channel. In some embodiments,transfer gate ST0 may be formed using polysilicon.

In some embodiments, transfer gate TX0 may be configured to controltransfer of charge carriers from charge storage region SD0 to readoutregion FD in the manner described for transfer gate ST0 in connectionwith photodetection region PPD and charge storage region SD0. Forexample, following a plurality of collection periods during which chargecarriers are transferred from photodetection region PPD to chargestorage region SD0, charge carriers stored in charge storage region SD0may be transferred to readout region FD to be read out for processing.

In some embodiments, transfer gate REJ may be configured to controltransfer of charge carriers from photodetection region PPD to drainregion D in the manner described for transfer gate ST0 in connectionwith photodetection region PPD and charge storage region SD0. Forexample, excitation photons from the excitation light source may reachphotodetection region PPD before fluorescent emission photons from thesample well 1-108 reach photodetection region PPD. In some embodiments,the integrated device 1-102 may be configured to control transfer gateREJ to transfer charge carriers generated in photodetection region PPDin response to the excitation photons to drain region D during a drainperiod following an excitation light pulse and preceding reception offluorescent emission charge carriers.

In some embodiments, pixel 1-112 may be electrically coupled to acontrol circuit of integrated device 1-102, and/or of a system thatincludes integrated device 1-102, and configured to receive controlsignals at transfer gates REJ, ST0, and TX0. For example, metal lines ofmetal layers 1-240 may be configured to carry the control signals topixels 1-112 of the integrated device 1-102. In some embodiments, asingle metal line carrying a control signal may be electrically coupledto a plurality of pixels 1-112, such as an array, subarray, row, and/orcolumn of pixels 1-112. For example, each pixel 1-112 in an array may beconfigured to receive a control signal from a same metal line and/or netsuch that the row of pixels 1-112 is configured to drain and/or collectcharge carriers from photodetection region PPD at the same time.Alternatively or additionally, each row of pixels 1-112 in the array maybe configured to receive different control signals (e.g., row-selectsignals) during a readout period such that the rows read out chargecarriers one row at a time.

FIG. 1-3 is a circuit diagram of pixel 1-112, according to someembodiments. In FIG. 1-3, transfer gate REJ is the gate of a transistorcoupling photodetection region PPD to drain region D, transfer gate ST0is the gate of a transistor coupling photodetection region PPD to chargestorage region SD0, and transfer gate TX0 is the gate of a transistorcoupling charge storage region SD0 to readout region FD. As shown inFIG. 1-3, pixel 1-112 further includes a reset (RST) transfer gatecoupled to readout region FD and configured for coupling to a powersupply voltage VDDP, and a row select (RS) transfer gate coupled betweenreadout region FD and a bitline. When the integrated device 1-102 iscoupled to a power source (e.g., at least a DC power supply), transfergate RST may be coupled to power supply voltage VDDP, which is suppliedby the power source and/or regulated by a voltage regulator ofintegrated device 1-102. For example, transfer gate RST may beconfigured to cause charge carriers to flow from readout region FDand/or from charge storage region SD0 via transfer gate TX0 and readoutregion FD, to power supply voltage VDDP.

In some embodiments, transfer gate RST may be configured to reset avoltage of readout region FD. For example, when a reset signal isapplied to transfer gate RST, transfer gate RST may bias the transferchannel electrically coupling readout region FD to power supply voltageVDDP, thereby increasing the conductivity of the transfer channel andtransferring charge carriers from readout region FD to power supplyvoltage VDDP. In some embodiments, reset transfer gate RST may befurther configured to reset the voltage of charge storage region SD0.For example, when a reset signal is applied to reset transfer gate RSTand a control signal is applied to transfer gate TX0, transfer gate TX0may transfer charge carriers in charge storage region SD0 to readoutregion FD and transfer gate RST may transfer the charge carriers topower supply voltage VDDP. In some embodiments, integrated device 1-102may be configured to reset readout region FD and charge storage regionSD0 before collecting and reading out charge carriers. For example,integrated device 1-102 may be configured to reset readout region FD andthen reset charge storage region SD0 before collecting and reading outcharge carriers.

In some embodiments, transfer gate RS may be configured to, in responseto a row select control signal, transfer charge carriers from readoutregion FD to the bitline for processing. In some embodiments, thebitline may be coupled to processing circuitry on the integrated device1-102 and/or an external circuit configured to receive a voltage levelindicative of charge carriers read out to readout region FD. Forexample, one bitline may be electrically coupled between each pixel1-112 of an array and processing circuitry. In some embodiments, theprocessing circuitry may include an analog-to-digital converter (ADC).In some embodiments, integrated device 1-102 may be configured to resetthe voltage of readout region FD of each pixel before reading out chargecarriers. For example, integrated device 1-102 may be configured toreset the voltage of readout region FD, sample the voltage, transfercharge carriers into readout region FD, and sample the voltage again. Inthis example, the second sampled voltage may be indicative of a numberof the charge carriers transferred into readout region FD when comparedto the first sampled voltage. In some embodiments, integrated device1-102 may be configured to read out charge carriers from each pixel1-112 to the bitline sequentially, such as row by row and/or column bycolumn (e.g., in response to receiving row select control signals).

It should be appreciated that some arrays of pixels 1-112 may havemultiple bitlines electrically coupled to different ones and/or groupsof pixels 1-112, such as with one bitline coupling a first column ofpixels 1-112 to first processing circuitry and another bitline couplinga second column of pixels 1-112 to second processing circuitry, and soon. In some embodiments, pixels of multiple columns may be read out torespective processing circuitry at the same time. For example, a firstpixel of each column may be read out to the respective processingcircuitry at the same time, and then a second pixel of each column maybe read out to the respective processing circuitry at the same time. Itshould be appreciated that, in some embodiments, processing circuitrymay be provided for each row of the array as an alternative or inaddition to each column. In some embodiments, integrated device 1-102may include multiple units of processing circuitry, such as each beingelectrically coupled to a bitline.

It should be appreciated that, in accordance with various embodiments,transfer gates described herein may include semiconductor material(s)and/or metal, and may include a gate of a field effect transistor (FET),a base of a bipolar junction transistor (BJT), and/or the like. Itshould be appreciated that control signals described herein applied tothe various transfer gates may vary in shape and/or voltage, such asdepending on the electric potential of the semiconductor region and ofthe regions electrically coupled to the semiconductor region (e.g.,neighboring regions).

FIG. 1-4 is a diagram showing example charge transfer in pixel 1-112,according to some embodiments. In some embodiments, operation of pixel1-112 may include one or more collection sequences. An examplecollection sequence is shown in FIG. 1-4 including a first collectionperiod 1-1, a first readout period 1-2, a second collection period 1-3,and a second readout period 1-4. In some embodiments, each collectionperiod of the collection sequence may be preceded by a drain period, asdescribed further herein. In some embodiments, operation of pixel 1-112may include one or multiple iterations of the collection sequence shownin FIG. 1-4. In some embodiments, the collection sequence may becoordinated with the excitation of samples in the sample wells 1-108.For example, a single control circuit may be configured to control theexcitation light source and operation of pixels 1-112.

In some embodiments, the first collection period 1-1 may includereceiving a first plurality of fluorescent emission photons atphotodetection region PPD. For example, first collection period 1-1 mayoccur in response to a pulse of excitation light that illuminates asample well 1-108 configured to emit fluorescent emission photons towardphotodetection region PPD. As shown in FIG. 1-4, photodetection regionPPD may be configured to generate charge carriers Q1 in response to theincident fluorescent emission photons and transfer charge carriers Q1 tocharge storage region SD0 during the first collection period 1-1. Insome embodiments, excitation photons may reach photodetection region PPDduring a drain period immediately following the excitation pulse butbefore first collection period 1-1, during which charge carriersgenerated in photodetection region PPD in response to the excitationphotons may be transferred to drain region D. In some embodiments,collection period 1-1 may be repeated multiple times in response tomultiple respective excitation pulses, and charge carriers Q1 may beaccumulated in charge storage region SD0 over the course of thecollection periods 1-1. In some such embodiments, each collection period1-1 may be preceded by a drain period. In some embodiments, thecollection periods 1-1 and/or drain periods preceding each collectionperiod 1-1 may occur at the same time for each pixel of an array,subarray, row, and/or column of the integrated device 1-102.

In some embodiments, the first readout period 1-2 may occur followingone or more collection periods 1-1 during which charge carriers Q1 areaccumulated in charge storage region SD0. As shown in FIG. 1-4, duringthe first readout period 1-2, charge carriers Q1 stored in chargestorage region SD0 may be transferred to readout region FD to be readout for processing. In some embodiments, the readout period 1-2 may beperformed using correlated double sampling (CDS) techniques. Forexample, a first voltage of readout region FD may be read out at a firsttime, followed by a reset of the readout region FD (e.g., by applying areset signal to transfer gate RST) and the transfer of charge carriersQ1 from charge storage region SD0 to readout region FD, and a secondvoltage of readout region FD may be read out at a second time followingthe transfer of charge carriers Q1. In this example, the differencebetween the first and second voltages may indicate a quantity of chargecarriers Q1 transferred from charge storage region SD0 to readout regionFD. In some embodiments, the first readout period 1-2 may occur at adifferent time for each row, column, and/or pixel of an array. Forexample, by reading out pixels one row or column at a time, a singleprocessing line may be configured to process readout of each row orcolumn in sequence rather than dedicating a processing line to eachpixel to read out simultaneously. In other embodiments, each pixel of anarray may be configured to read out at the same time, as a processingline may be provided for each pixel of the array. According to variousembodiments, charge carriers read out from the pixels may indicatefluorescence intensity, lifetime, spectral, and/or other suchfluorescence information of the samples in the sample wells 1-108.

In some embodiments, the second collection period 1-3 may occur in themanner described for collection period 1-1. For example, following thefirst readout period 1-2, one or more second collection periods 1-3 mayfollow one or more respective excitation pulses, such as with a drainperiod preceding each collection period 1-3. As shown in FIG. 1-4,during the second collection period(s) 1-3, charge carriers Q2 generatedin photodetection region PPD may be transferred to charge storage regionSD0. In some embodiments, a delay between each excitation pulse andcorresponding collection period 1-3 may be different from a delaybetween each excitation pulse and corresponding collection period 1-1.For example, by collecting charge carriers during a different timeperiod following the excitation pulse during different collectionperiods, charge carriers read out from the collection periods 1-1 and1-3 may indicate fluorescence lifetime information of the samples in thesample wells 1-108. In some embodiments, the second collection period(s)1-3 may be followed by a second readout period 1-4 during which chargecarriers accumulated in charge storage region SD0 over the course of thesecond collection period(s) may be read out in the manner describedherein for the first readout period 1-2.

According to various embodiments, pixels described herein may includemore than one charge storage region, such as two, three, four, or fivecharge storage regions. For example, a pixel may include a second chargestorage region electrically coupled between charge storage region SD0and readout region FD, with transfer channels electrically couplingcharge storage region SD0 to the second charge storage region and thesecond charge storage region to readout region FD. In this example,transfer gate TX0 may be configured to control the transfer of chargecarriers from charge storage region SD0 to the second charge storageregion, and the pixel may include another transfer gate configured tocontrol the transfer of charge carriers from the second charge storageregion to readout region FD.

III. Charge Carrier Depletion Techniques

The inventors have developed techniques for inducing a charge carrierdepletion in the photodetection region of a pixel. In some embodiments,a pixel may have one or more charged and/or biased regions configured toinduce the charge carrier depletion in the photodetection region. Forexample, the charged and/or biased region may include a charge layerconfigured to induce an intrinsic charge carrier depletion in thephotodetection region. In this example, the charge layer may bepositioned on one or more sides of the photodetection region and/or onone or more sides of the pixel boundary. Alternatively or additionally,the charged and/or biased region may include a metal region configuredto receive a voltage bias to induce the charge carrier depletion. Themetal region may be positioned on one or more sides of thephotodetection region and/or on one or more sides of the pixel boundary.In either example, the charged and/or biased region may attract chargecarriers from within the photodetection region, thereby depleting thephotodetection region of charge carriers. In some embodiments, thephotodetection region may have fewer than 10¹² charge carriers per cubiccentimeter (cm³), fewer than 10⁶ charge carriers per cm³, and/or fewerthan 10³ charge carriers per cm³ when the photodetection region isdepleted of charge carriers. In some embodiments, a pixel may includemultiple charged and/or biased regions positioned on respective sides ofthe photodetection region. In accordance with various embodiments, themultiple charged and/or biased regions may form a continuous structureor may be separate from one another.

FIG. 2-1A is a top view of an array of pixels 2-112 a with shieldportions that may be included in the integrated device 1-102, accordingto some embodiments. In some embodiments, pixels 2-112 a may beconfigured in the manner described herein for pixel 1-112. For example,as shown in FIG. 2-1A, each pixel 2-112 a includes a photodetectionregion PPD. In FIG. 2-1A, each pixel 2-112 a also includes multiple C/Bregions positioned about the pixel 2-112 a and a shield portion.

In some embodiments, photodetection regions PPD pixels 2-112 a may beconfigured to receive incident photons at the top side shown in FIG.2-1A. In some embodiments, the shield portions may be configured toblock incident photons from reaching other components of pixels 2-112 adisposed below the shield portions, such as charge storage regions,readout regions, transfer gates, and/or circuitry. For example, theshield portions may be formed using an optically opaque material such asmetal (e.g., aluminum or tungsten).

In FIG. 2-1A, the C/B regions of each pixel are positioned on multiplerespective sides of the photodetection region PPD. The C/B regions maybe alternatively or additionally positioned on multiple respective sidesof the boundary of each pixel 2-112 a. In some embodiments, the C/Bregions of each pixel may be configured to induce a charge carrierdepletion in photodetection region PPD. For example, one or more of theC/B regions may include a charge layer configured to induce an intrinsiccharge carrier depletion in photodetection region PPD. In someembodiments, the charge layer may include an oxide layer and ametal-oxide compound. In this example, the oxide layer may provideisolation between the photodetection region PPD and the metal-oxidecompound. In accordance with various embodiments, the metal-oxidecompound may be aluminum oxide (Al₂O₃), hafnium dioxide (HfO₂), titaniumdioxide (TiO₂), tantalum pentoxide (Ta₂O₅), or any combination thereof.It should be appreciated that other charged oxide materials, such as anyother metal-oxides, configured to generate an accumulation layer of freecharge carriers, may be used. In some embodiments, C/B regionspositioned between two or more pixels may be configured to induce acharge carrier depletion in the photodetection region of some or each ofthe pixels.

Alternatively or additionally, the C/B regions may include one or moremetal regions configured to receive a voltage bias that induces thecharge carrier depletion in photodetection region PPD. For example, themetal region(s) may be configured for electrically coupling to a voltagesource and/or voltage regulator of integrated device 1-102 and/or anexternal power supply when the integrated device 1-102 is connected tothe power supply. In some embodiments, a pixel may have a combination ofcharge layers and metal regions configured to receive a voltage biaswith the combination configured to induce the charge carrier depletionin photodetection region PPD.

FIG. 2-1B is a top view of an array of pixels 2-112 b that may beincluded in the integrated device 1-102 including shield portions in analternative configuration, according to some embodiments. Pixels 2-112 bmay be configured in the manner described herein for pixels 2-112 a inconnection with FIG. 2-1A. For example, pixels 2-112 b includephotodetection regions PPD and shield portions. In some embodiments,pixels 2-112 b may also include C/B regions below the shield portionsand configured in the manner described herein in connection with FIG.2-1A. In some embodiments, the shield portions shown in FIG. 2-1B may beconfigured to block incident photons from reaching the C/B regions. Forexample, in FIG. 2-1B, the shield portions may cover the C/B regionssuch that the shield portions block photons incident on the C/B regionsin the first direction Dir1 (FIG. 1-2) from reaching the C/B regions.

FIG. 2-1C is a top view of an array of pixels 2-112 c that may beincluded in the integrated device 1-102 including shield portions in afurther alternative configuration, according to some embodiments. Pixels1-112 c may be configured in the manner described herein for pixels2-112 b in connection with FIG. 2-1B. For example, the shield portionsshown in FIG. 2-1C are shown in a manner configured to block incidentphotons from reaching the C/B regions of the pixels 1-112 c. Also shownin FIG. 2-1C, the shield portions leave additional portions of thepixels 1-112 c exposed to incident photons. For example, the shieldportions may not block incident photons from reaching the charge storageregion(s) of the pixel. The inventors recognized that, in some cases,incident photons may be absorbed in the depth of the pixel beforereaching the charge storage region(s). Moreover, the inventorsrecognized that leaving the additional portions of the pixel exposed toincident photons through the shield portions increases the amount ofphotons received in photodetection region PPD, thereby increasing thenumber of fluorescent photons that can be received and fluorescentcharge carriers that can be collected in the charge storage region(s).

FIG. 2-2A is a top view of a pixel 2-112 a of the array shown in FIG.2-1A, according to some embodiments. As shown in FIG. 2-2A, the C/Bregions of the pixel 2-112 a include a first region C/B₁ positioned on afirst side of the photodetection region PPD, a second region C/B₂positioned on a second side of the photodetection region PPD, a thirdregion C/B₃ positioned on a third side of the photodetection region PPD,and a fourth region C/B₄ positioned on a fourth side of thephotodetection region PPD. The first region C/B₁ is also positioned on afirst side of the boundary of the pixel 2-112 a, the second region C/B₂is positioned on a second side of the boundary of the pixel 2-112 a, thefourth region C/B₄ is positioned on a third side of the boundary of thepixel 2-112 a, and a fifth region C/B₅ is positioned on a fourth side ofthe boundary of the pixel 2-112 a. The fifth region C/B₅ is alsopositioned on the third side of the photodetection region PPD. Forexample, in embodiments that do not include third region C/B₃,photodetection region PPD may be surrounded on four sides by regionsC/B₁, C/B₂, C/B₄, and C/B₅, respectively. In some embodiments, a sixthregion C/B₆ may be positioned on a fifth side of the boundary of pixel2-112 a and/or of photodetection region PPD, such as beforephotodetection region PPD in the direction in which photodetectionregion PPD is configured to receive incident photons (e.g., the firstdirection Dir1). In FIG. 2-2A, C/B regions positioned around the shieldportion are covered by the shield portion, which may be configured toblock incident photons from reaching the regions covered by the shieldportion.

FIG. 2-2B is a top view of a pixel 2-112 b of the array shown in FIG.2-1B, according to some embodiments. As shown in FIG. 2-2A, the C/Bregions are configured as described herein for pixel 2-112 a inconnection with FIG. 2-2A, and the shield portion also covers the first,second, third, and fourth regions C/B₁, C/B₂, C/B₃, and C/B₄ on thefirst, second, third, and fourth sides of the photodetection region PPD.

FIG. 2-2C is a top view of a pixel 2-112 c of the array shown in FIG.2-1C, according to some embodiments. As shown in FIG. 2-2C, the C/Bregions may be configured as described herein for pixel 2-112 a inconnection with FIG. 2-2A, except that pixel 2-112 c does not includeregion C/B₃. Also shown in FIG. 2-2C, the photodetection region PPDextends from region C/B₄ to region C/B₅. In some embodiments, the shieldportions shown in FIG. 2-2C may be configured to block incident photonsfrom reaching the C/B regions while exposing more of photodetectionregion PPD to incident photons. In FIG. 2-2C, the opening in the shieldportions is rectangular, but the opening may have any shape such as asquare according to various embodiments.

It should be appreciated that, in some embodiments, pixels 2-112 a and2-112 b may not include region C/B₃ and/or may have photodetectionregion PPD extend from region C/B₄ to region C/B₅.

FIG. 2-3 is a layout sketch of an example pixel 2-312 that may beincluded in the arrays of FIGS. 2-1A, 2-1B, or 2-1C, according to someembodiments. For example, in some embodiments, pixels 2-112 a and 2-112b may be further configured in the manner described herein for pixel2-312. As shown in FIG. 2-3, pixel 2-312 includes photodetection regionPPD, charge storage region SD0, drain region D, and transfer gates ST0,TX0, and REJ. In some embodiments, transfer gate RS may be configured asdescribed herein for FIG. 1-3. In some embodiments, the source follower(SF) transfer gate may be electrically coupled to readout region FD suchthat a voltage level of readout region FD may be sampled via transfergate RS. In some embodiments, the shield portion of pixel 2-312 may beconfigured to block incident photons from reaching charge storage regionSD0, drain region D, and transfer gates ST0, TX0, REJ, RS, and SF.

In some embodiments, photodetection region PPD of pixel 2-312 may beconfigured to induce an intrinsic electric field in a direction fromphotodetection region PPD toward charge storage region SD0, as describedfurther herein with reference to FIGS. 2-4A and 2-4B. FIG. 2-4A is alayout sketch of an alternative example pixel 2-412 that may be includedin the arrays of FIGS. 2-1A, 2-1B, or 2-1C, according to someembodiments. Pixel 2-412 may be configured in the manner describedherein for pixel 2-312. As shown in FIG. 2-4A, pixel 2-412 similarlyincludes photodetection region PPD, charge storage region SD0, drainregion D, readout region FD, and transfer gates ST0, TX0, REJ, RS, andSF.

In some embodiments, photodetection region PPD may have a triangulardopant configuration configured to induce an intrinsic electric fieldfrom photodetection region PPD toward charge storage region SD0 anddrain region D. As shown in FIG. 2-4A, photodetection region PPDincludes a mask having a triangular opening, with a base of thetriangular opening positioned at a first end of photodetection regionPPD adjacent charge storage region SD0 and drain region D and an apex ofthe triangular opening positioned on a second end of photodetectionregion PPD opposite charge storage region SD0 and drain region D. Insome embodiments, photodetection region PPD may be doped through thetriangular opening, resulting in a triangular dopant configurationhaving the shape of the triangular opening. In some embodiments, thetriangular dopant configuration may induce an intrinsic electric fieldin a direction from the second end toward the first end, therebyincreasing the rate and efficiency of transferring charge carriers fromphotodetection region PPD to charge storage region SD0 and drain regionD.

FIG. 2-4B is a layout sketch of pixel 2-412, according to someembodiments. FIG. 2-4B further illustrates regions C/B₁, C/B₂, C/B₄, andC/B₅ positioned on the sides of the boundary of pixel 2-412, asdescribed herein for pixels 2-112 a and 2-112 b in connection with FIGS.2-1A to 2-2B. Although not shown in FIG. 2-4A, pixel 2-412 may alsoinclude Row Select (RS) and/or Source Follower (SF) transfer gatesand/or a C/B₃ region positioned on the side of photodetection region PPDbetween photodetection region PPD and charge storage region SD0 anddrain region D. Although not shown in FIG. 2-4B, it should beappreciated that, in some embodiments, the charge layer(s) of the C/Bregions of pixels described herein may be configured for coupling to apower supply voltage, such as at ground potential, to depletephotodetection region PPD of charge carriers. For example, the chargelayer(s) may be exposed at the face of the integrated device thatsupports the transfer gates to allow connections between the chargelayer(s) and metal routing to receive the power supply voltage.Alternatively or additionally, some or all pixels of the integrateddevice may include trenches for conductively coupling the power supplyvoltage to an edge of the pixel array where the pixels of the array maybe connected to the power supply voltage.

FIG. 2-5A is a layout sketch of an example pixel 2-512 a havingdiscontinuous C/B regions that may be included in the arrays of FIGS.2-1A, 2-1B, and 2-1C, according to some embodiments. Pixel 2-512 a maybe configured in the manner described herein for pixel 2-312 and/or anyother pixel described herein. For example, pixel 2-512 a is shown inFIG. 2-5A including photodetection region PPD, drain region D, chargestorage region SD0, readout region FD, and transfer gates REJ, ST0, RST,RS, and SF. Also shown in FIG. 2-5A, pixel 2-512 a includes barrier BPW,which may be configured to block incident charge carriers from reachingcharge storage region SD0, as described further herein. Also shown inFIG. 2-5A, pixel 2-512 a includes a p-doped well that may support someor all of the transistors having transfer gates RST, RS, SF, and TX0. Insome embodiments, the p-well may be configured (e.g., expanded by dopinga larger area of pixel 2-512 a) to block incident charge carriers fromreaching charge storage region SD0. Also shown in FIG. 2-5A, pixel 2-512a includes barriers DPI positioned between pixel 2-512 a and adjacentpixels of the array including pixel 2-512 a. For example, barriers DPImay be configured to block charge carriers from traveling betweenadjacent pixels of the array, as described further herein.

In some embodiments, some or all C/B regions may be discontinuous on atleast one side of a pixel. For example, as shown in FIG. 2-5A, regionsC/B₁ and C/B₂ of pixel 2-512 a running parallel to the direction fromphotodetection region PPD to charge storage region SD0 are continuousand regions C/B₄ and C/B₅ running perpendicular to the direction ofregions C/B₁ and C/B₂ are discontinuous, with gaps separating regionsC/B₄ and C/B₅ from regions C/B₁ and C/B₂.

FIG. 2-5B is a layout sketch of an alternative example pixel 2-512 bhaving discontinuous C/B regions that may be included in the arrays ofFIGS. 2-1A, 2-1B, and 2-1C, according to some embodiments. Pixel 2-512 bmay be configured in the manner described herein for pixel 2-512 aand/or any other pixel described herein. As shown in FIG. 2-5B, pixel2-512 b further includes an auxiliary gate REJ′ coupled to drain regionD. In some embodiments, auxiliary gate REJ′ may be part of adiode-connected transistor connected between drain region D and a metalline configured to electrically couple drain region D to a power supplyvoltage. It should be appreciated that other pixels described herein mayadditionally include auxiliary gate REJ'.

Similar to pixel 2-512 a shown in FIG. 2-5A, some C/B regions of pixel2-512 b are discontinuous. For example, shown in FIG. 2-5B, regions C/B₁and C/B₂ of pixel 2-512 b running parallel to the direction fromphotodetection region PPD to charge storage region SD0 are discontinuousand the regions C/B₄ and C/B₅ running perpendicular to the direction ofregions C/B₁ and C/B₂ are continuous, with gaps separating regions C/B₁and C/B₂ from regions C/B₄ and C/B₅. It should be appreciated that otherpixels described herein may have discontinuous C/B regions as describedherein for pixels 2-512 a and 2-512 b.

Also shown in FIG. 2-5B, pixel 2-512 b region C/B₃ is positioned betweenphotodetection region and charge storage region SD0 and terminatesbefore drain region D. In some embodiments, region C/B₃ of other pixelsdescribed herein may be configured as shown in FIG. 2-5B for pixel 2-512b. In some embodiments, region C/B₃ may be omitted, such as shown inFIG. 2-2C.

FIG. 2-6A is a cross-sectional schematic view of an example pixel 2-612a that may be included in the arrays of FIGS. 2-1A or 2-1B, according tosome embodiments. In FIG. 2-6A, regions C/B₃-C/B₅, charge storage regionSD0, readout region FD, and transfer gates TX0 and ST0 are positioned,in the first direction Dir1, after the shield portion of pixel 2-612 a.In some embodiments, pixel 2-612 a may have a thickness in the firstdirection Dir1 between the shield portion and transfer gates ST0 and TX0of less than 10 microns, such as less than 6 microns, and/or between 3and 6 microns.

In some embodiments, photodetection region PPD may include multiplesub-regions positioned after one another in the first direction Dir1.For example, in FIG. 2-6A, photodetection region PPD includes a firstsub-region and a second sub-region positioned after the first sub-regionin the first direction Dir1. The first sub-region extends, in the firstdirection Dir1, until the ends of regions C/B₃ and C/B₄. It should beappreciated that, in some embodiments, the first sub-region may end, inthe first direction Dir1, before or after the ends of regions C/B₃ andC/B₄. In FIG. 2-6A, the C/B regions are elongated, in the firstdirection Dir1, alongside photodetection region PPD.

In some embodiments, regions C/B₃ and/or C/B₄ may be configured toinduce a charge carrier depletion in the first sub-region ofphotodetection region PPD. For example, regions C/B₃ and/or C/B₄ mayinclude charge layers configured to induce an intrinsic charge carrierdepletion in the first sub-region. Alternatively or additionally,regions C/B₃ and/or C/B₄ may include metal regions configured to inducea charge carrier depletion in the first sub-region when a voltage biasis received at the metal regions. In some embodiments, transfer gate ST0(and/or drain gate REJ, not shown in FIG. 2-6A) may be configured toinduce a charge carrier depletion in the second sub-region when acontrol signal is received at the transfer gate. In some embodiments,the charge carrier depletion may facilitate propagation of chargecarriers from photodetection region PPD toward charge storage regionSD0.

In FIG. 2-6A, pixel 2-612 a also includes barrier LPW, with readoutregion FD positioned, in the first direction Dir1, after barrier LPW,and barrier BPW, with charge storage region SD0 positioned, in the firstdirection Dir1, after barrier BPW. In some embodiments, barriers LPW andBPW may be configured to block charge carriers in pixel 2-612 a fromreaching readout region FD and charge storage region SD0, respectively,other than along transfer channels electrically coupling the regions toone another. In some embodiments, barriers LPW and BPW may be formed bydoping regions of pixel 2-612 a to have an opposite conductivity typefrom photodetection region PPD, charge storage region SD0, and readoutregion FD. For example, photodetection region PPD, charge storage regionSD0, and readout region FD may be n-type doped, and barriers LPW and BPWmay be p-type doped.

In FIG. 2-6A, pixel 2-612 a also includes barriers DPI positionedbetween the C/B regions and other regions of pixel 2-612 a, such asbetween region C/B₄ and photodetection region PPD, between region C/B₃and photodetection region PPD, and between region C/B₅ and readoutregion FD. In some embodiments, barriers LPW and BPW may be formed bydoping regions of pixel 2-612 a to have an opposite conductivity typefrom photodetection region PPD, charge storage region SD0, and readoutregion FD.

Pixel 2-612 a also includes a filter layer and an optical component. Insome embodiments, the filter layer may be formed by doping a region ofthe pixel 2-612 a before the shield in the first direction Dir1 with asame conductivity type as photodetection region PPD, charge storageregion SD0, and readout region FD. In some embodiments, the opticalcomponent may be a microdisk. For example, the microdisk may be adielectric structure configured to couple in florescence emissionphotons emitted by a sample and re-emit photons toward thephotodetection region PPD. In some embodiments, the microdisk mayefficiently couple photons incident along oblique directions withrespect to the first direction Dir1 and re-emit the photons toward thephotodetection region PPD in the first direction Dir1.

In some embodiments, a pixel including C/B regions may be manufacturedby forming C/B regions to induce a charge carrier depletion in thephotodetection region. For example, one or more charge layers (e.g.,metal-oxide compounds) may be deposited in the pixel to form the C/Bregions. In some embodiments, an oxide layer may be deposited in thepixel, and the charge layer(s) may be deposited over the oxide layer.For example, the oxide layer may include silicon dioxide (SiO₂). In someembodiments, after the charge layer(s) have been deposited over theoxide layer, additional oxide (e.g., SiO₂) may be deposited in thepixel. In some embodiments, metal-oxide compounds described herein maybe deposited conformally, such as by conformal atomic layer deposition(ALD), and/or by chemical vapor deposition (CVD). For example, ALD ofmetal-oxide compounds described herein may have a thickness of 50Angstroms, and CVD metal-oxide compounds described herein may have athickness of 500 Angstroms. In some embodiments, prior to deposition, amasked etch may be performed to form at least one trench for depositioninto the trench. It should be appreciated that any suitable chargedmaterials (e.g., positively charged for depleting electrons) may be usedto form the C/B regions for depleting photodetection region PPD, such asmaterials compatible with conformal deposition processes (e.g., ALD). Asone example, such materials may be substantially or entirely free ofelectrons from atomic bonding and/or lattice sites, resulting inpositive charge.

In some embodiments, one or more metal regions may be deposited in thepixel to form the C/B regions, with the one or more metal regions beingconfigured for coupling to a voltage bias to induce the charge carrierdepletion in the photodetection region. In some embodiments, barriersDPI may be formed by doping regions around the C/B regions to have anopposite conductivity type from the photodetection region. In someembodiments, the C/B regions may induce an intrinsic charge carrierdepletion in the photodetection region (e.g., in the first sub-region)upon formation of the pixel (e.g., without applying an external electricfield to the pixel). In some embodiments, C/B regions of some or allpixels in an integrated device may be formed simultaneously. Forexample, any or each of regions C/B₁, C/B₂, C/B₃, C/B₄, and/or C/B₅ maybe formed during a same manufacturing step, such as a same conformal ALDand/or CVD step. In some embodiments, a sixth region C/B₆ may be formedduring an ALD and/or CVD step preceding or following the step duringwhich the other C/B regions are formed.

In some embodiments, the C/B regions may be formed from an opposite sideof the integrated device, in the first direction Dir1, than thephotodetection region, charge storage region(s), and/or readout region.For example, the photodetection region, charge storage region(s), and/orreadout regions may be doped on a first face, in the first directionDir1, of the integrated device, and the C/B/ regions may be formed from(e.g., deposited from) a second face, in the first direction Dir1, ofthe integrated device.

FIG. 2-6B is a cross-sectional schematic view of an alternative examplepixel 2-612 b that may be included in the arrays of FIGS. 2-1A or 2-1B,according to some embodiments. As shown in FIG. 2-6B, pixel 2-612 b maybe configured in the manner described herein for pixel 2-612 a inconnection with FIG. 2-6A, except pixel 2-612 b may not include afilter. The inventors recognized that, in some embodiments, pixelsdescribed herein may not include a filter, such as when charge transferoccurs in the pixel at a fast enough rate.

FIG. 2-7A is a cross-sectional schematic view of an example pixel 2-712a that may be included in the arrays of FIG. 2-1A or 2-1B, according tosome embodiments. In some embodiments, pixel 2-712 a may be configuredin the manner described herein for pixel 2-312. In FIG. 2-7A,photodetection region PPD extends between region C/B₄ to region C/B₅.For example, pixel 2-712 a may not include region C/B₃. The inventorshave recognized that positioning photodetection region PPD to extendbetween region C/B₄ to region C/B₅, and/or such that at least a portionof photodetection region PPD is positioned, in the first direction Dir1,before charge storage region SD0 and/or readout region FD, preventsincident photons and/or charge carriers from entering undesired portionsof pixel 2-712 a. For example, the incident photons and/or chargecarriers may be transferred to the drain region D and/or to chargestorage region SD0 via photodetection region PPD.

As shown in FIG. 2-7A, photodetection region PPD of pixel 2-712 aincludes first and second sub-regions, with the first sub-regionextending, in the first direction Dir1, to the ends of regions C/B₄ andC/B₅ and/or to the barriers LPW and/or BPW. For example, the firstsub-region may end, in the first direction Dir1, at a barrier or at theend of region C/B₄ or C/B₅, whichever the first sub-region reachesfirst. In FIG. 2-7A, regions C/B₄ and/or C/B₅ may be configured toinduce a charge carrier depletion in the first sub-region as describedherein in connection with FIG. 2-6A. In FIG. 2-7A, the C/B regions areelongated, in the first direction Dir1, alongside photodetection regionPPD.

FIG. 2-7B is a cross-sectional schematic of a view of an alternativeexample pixel 2-712 b that may be included in the array of FIG. 2-1A or2-1B, according to some embodiments. As shown in FIG. 2-7B, pixel 2-712b may be configured in the manner described herein for pixel 2-712 a inconnection with FIG. 2-7A, except that pixel 2-712 b may not include afilter, such as described herein for pixel 2-612 b in connection withFIG. 2-6B.

FIG. 2-8 is a cross-sectional schematic view of an example pixel 2-812that may be included in the array of FIG. 2-1A or 2-1B, according tosome embodiments. As shown in FIG. 2-8, pixel 2-812 may be configured inthe manner described herein for pixel 2-612 a including in connectionwith FIG. 2-6A. Additionally, as shown in FIG. 2-8, barriers DPI mayextend in the first direction Dir1 only part away along a depth of pixel2-812. For example, barriers DPI may terminate alongside photodetectionregion PPD part-way through a depth of photodetection region PPD in thefirst direction Dir1.

FIG. 2-9 is a cross-sectional schematic view of pixel 2-112 c shown inFIG. 2-2C, according to some embodiments. As shown in FIG. 2-9, pixel2-112 c may be configured in the manner described herein for pixel 2-712a including in connection with FIG. 2-7A, but with photodetection regionPPD exposed through the shield portions on the side, in the firstdirection Dir1, that is configured to receive incident photons. Itshould be appreciated that some embodiments may include a filter asdescribed herein for pixel 2-612 a.

FIG. 2-10 is a cross-sectional schematic view of an example pixel2-1012, which may be included in the array of FIG. 2-1C, according tosome embodiments. As shown in FIG. 2-10, pixel 2-1012 may be configuredin the manner described herein for pixel 2-112 c including in connectionwith FIG. 2-9. As shown in FIG. 2-10, barriers DPI extend only part waythrough a depth of pixel 2-1012, as described herein for pixel 2-812 inconnection with FIG. 2-8. Also shown in FIG. 2-10, the C/B regions ofpixel 2-812 may extend, in the first direction Dir1, alongsidephotodetection region PPD from a first end of photodetection region PPDproximate the shield portions to a second end of photodetection regionPPD proximate the transfer gates ST0 and TX0. In some embodiments, theC/B regions may terminate before a pinning layer of the photodetectionregion PPD at the second end. The inventors recognized that having theC/B regions extend from a first end of photodetection region PPD to asecond end of photodetection region PPD provides greater optical andelectrical isolation between adjacent pixels. In some embodiments, pixel2-1012 may include a filter such as described herein for pixel 2-612 ain connection with FIG. 2-6A.

FIG. 2-11 is a cross-sectional schematic view of an example pixel 2-1112that may be included in the array of FIG. 2-1C, according to someembodiments. As shown in FIG. 2-11, pixel 2-1112 may be configured inthe manner described herein for pixel 2-1012 including in connectionwith FIG. 2-10. In FIG. 2-11, pixel 2-1112 includes multiple barriersSTI and DPI elongated, in the first direction Dir1, alongside thephotodetection region PPD. For example, barriers DPI and the C/B regionsmay terminate, in the first direction Dir1, at barriers STI. In someembodiments, one set of tools may be used to form the C/B regions fromthe side of pixel 2-1112 configured to receive incident photons, and adifferent set of tools may be used to form barrier STI at the other sideof pixel 2-1112 where the transfer gates are positioned.

It should be appreciated that techniques described herein in connectionwith pixels 2-112 a and/or 2-112 b may be used in embodiments of pixel2-112 c, and vice versa.

FIG. 2-13 is a layout sketch of an example pixel 2-1312 having multiplecharge storage regions that may be included in the arrays of FIGS. 2-1A,2-1B, and 2-1C, according to some embodiments. In some embodiments,pixel 2-1312 may be configured in the manner described herein for pixel2-512 a and/or any other pixel described herein. For example, in FIG.2-13, regions C/B₄ and C/B₅ of pixel 2-1312 are shown discontinuous andregions C/B₁ and C/B₂ are shown continuous.

As shown in FIG. 2-13, pixel 2-1312 includes first and second chargestorage regions SD0 and SD1, with second charge storage regionsincluding sub-regions SD1-0 and SD1-1, and with transfer gate TX0 ispositioned between first charge storage region SD0 and second chargestorage region SD1. Also shown in FIG. 2-13, pixel 2-1312 includestransfer gate TX1 positioned between second charge storage region SD1and readout region FD.

In some embodiments, charge storage region SD0 and sub-regions SD1-0 andSD1-1 of second charge storage region SD1 may have different electricpotential levels. For example, charge storage region SD0 may have afirst doping concentration, sub-region SD1-0 may have a second dopingconcentration higher than the first doping concentration, and sub-regionSD1-1 may have a third doping concertation higher than the second dopingconcentration.

FIG. 2-14 is a diagram showing example charge transfer in pixel 2-1312,according to some embodiments. As shown in FIG. 2-14, operation of pixel2-1312 may include multiple charge collection and transfer stepsperformed in time periods 2-1, 2-2, 2-3, 2-4, and 2-5.

In FIG. 2-14, operation of pixel 2-1312 may be cyclical. For example, asdescribed further herein, each operation cycle may be performed duringtime periods 2-1 to 2-4, and pixel operation during time period 2-5 maybe performed during time period 2-1 of a subsequent cycle (e.g.,simultaneously with steps performed during time 2-1 of the subsequentcycle).

In some embodiments, time period 2-1 may include one or more collectionsequences such as described herein for time period 1-1 in connectionwith FIG. 1-4. For example, as shown in FIG. 2-14, charge carriers Q1are received at charge storage region SD0 from photodetection region PPDduring period 2-1. In some embodiments, the transfer channelelectrically coupling charge storage region SD0 to charge storage regionSD1 may be biased during time period 2-1 such that an intrinsic electricpotential barrier prevents charge carriers from reaching charge storageregion SD1.

In some embodiments, time period 2-2 may include one or more transfersequences. For example, in FIG. 2-14, charge carriers Q1 are transferredfrom storage region SD0 to SD1 during time period 2-2. In someembodiments, the transfer channel electrically coupling photodetectionregion PPD to charge storage region SD0 may be biased during time period2-2 such that charge carriers are not received in charge storage regionSD0 from photodetection region PPD.

In some embodiments, time period 2-3 may include one or more readoutsequences. For example, during each readout sequence, integrated device1-102 may read out charge carriers from charge storage region SD1. Forexample, in FIG. 2-14, charge carriers Q1 are transferred from chargestorage region SD1 to readout region FD during period 2-3. In someembodiments, time period 2-3 may also include one or more collectionsequences performed in the manner described herein for time period 2-1.For example, In FIG. 2-14, charge carriers Q2 are received in chargestorage region SD0 from photodetection region PPD during time period2-3. In some embodiments, collection sequences performed during timeperiod 2-3 may include collection periods that are offset in time withrespect to the collection periods of time period 2-1. For example, thecollection periods of time period 2-3 may be timed to capture chargecarriers indicative of different characteristics (e.g., fluorescencelifetime) than the collection periods of time period 2-1.

In some embodiments, time period 2-4 may include one or more transfersequences performed in the manner described herein for time period 2-2.For example, in FIG. 2-14, charge carriers Q2 are transferred fromcharge storage region SD0 to charge storage region SD1 during timeperiod 2-4.

In some embodiments, time period 2-5 may include one or more readoutsequences and one or more collection sequences performed in the mannerdescribed herein for time period 2-3. For example, in FIG. 2-14, chargecarriers Q2 are transferred from charge storage region SD1 to readoutregion FD and charge carriers Q1′ are received at charge storage regionSD0 from photodetection region PPD during time period 2-5. In thisexample, receiving charge carriers Q1′ also occurs during time period2-1 of a subsequent cycle of operation, as time period 2-5 of theillustrated operation cycle overlaps, at least in part, with time period2-1 of the subsequent cycle (e.g., when charge carriers Q2 are read outfrom the particular pixel).

It should be appreciated that, in some embodiments, operation of pixelsdescribed herein may include time periods between the time periodsdescribed herein and/or may omit certain time periods described herein.It should also be appreciated that, in some embodiments, operation ofpixels described herein may not be cyclical, for example, by moving to anew time period (e.g., not any of time periods 2-1 through 2-5) aftertime period 2-5 is complete. In some embodiments, time periods describedherein may occur in a different order than described herein.

IV. Intrinsic Electric Field Techniques

The inventors have also developed techniques for inducing intrinsicelectric fields in a photodetection region of a pixel. In someembodiments, the photodetection region may be configured to induce anintrinsic electric field in a first direction (e.g., a direction fromthe sample well toward the photodetection region). For example, thephotodetection region may be configured to induce an intrinsic electricfield in a direction in which incident photons are received such thatcharge carriers generated in the photodetection region in response tothe incident photons may be transferred quickly and efficiently in thefirst direction. In some embodiments, the photodetection region mayinclude multiple layers positioned one after another in the firstdirection and having different intrinsic electric potential layers(e.g., due to having different dopant concentrations), thereby producingin an intrinsic electric field in the first direction.

In some embodiments, intrinsic electric fields may be combined withcharge carrier depletion, each facilitating propagation of chargecarriers from the photodetection region toward the charge storageregion(s). It should be appreciated, however, that these techniques maybe used alone or in any suitable combination, as embodiments describedherein are not so limited.

In some embodiments, pixels described herein may include aphotodetection region configured to induce an intrinsic electric fieldin the photodetection region in a first direction, as described furtherherein including with reference to FIG. 2-12. FIG. 2-12 is across-sectional schematic view of a portion of a pixel 2-1212 that maybe included in the array of FIG. 2-1A, 2-1B, or 2-1C, according to someembodiments. In FIG. 2-12, the portion of pixel 2-1212 includesphotodetection region PPD, charge storage region SD0, and transfer gateST0. In some embodiments, photodetection region PPD includes multiplelayers, such as Layers 1-3 indicated in FIG. 2-12, positioned one afteranother in the first direction Dir1. It should be appreciated thatphotodetection region PPD can have any number of layers, such as 4-10layers or any number of layers therein, as suitable for the particularapplication.

In some embodiments, photodetection region PPD may be configured toinduce an intrinsic electric field in the first direction Dir1. Forexample, the layers of photodetection region PPD may be configured tohave different intrinsic electric potential levels, such that thedifference between the electric potential levels induces an intrinsicelectric field. In this example, Layer 2 may have a higher dopantconcentration than Layer 1, and Layer 3 may have a higher dopantconcentration than Layer 2. In some embodiments, photodetection regionPPD may be n-type doped, and the intrinsic electric potential level ofLayer 3 may be higher than the intrinsic electric potential level ofLayer 2, and the intrinsic electric potential level of Layer 2 may behigher than the intrinsic electric potential level of Layer 1. As aresult, photoelectrons generated in photodetection region PPD may betransferred more quickly and efficiently in the first direction Dir1. Insome embodiments, photodetection region PPD may be p-type doped, and theintrinsic electric potential level of Layer 3 may be higher than theintrinsic electric potential level of Layer 2, and the intrinsicelectric potential level of Layer 2 may be higher than the intrinsicelectric potential level of Layer 1. As a result, photo-holes generatedin photodetection region PPD may be transferred more quickly andefficiently in the first direction Dir1.

In some embodiments, layer within a first sub-region of photodetectionregion PPD may have different electric potential levels from layerswithin a second sub-region of photodetection region PPD. For example,layers of a second sub-region positioned, in the first direction Dir1,after a first sub-region may have a higher dopant concentration thanlayers of the first sub-region.

In some embodiments, photodetection region PPD may be manufactured byforming the layers of photodetection region PPD to have differentintrinsic electric potential levels, such as by forming Layer 3 to havea higher dopant concentration than Layer 2, Layer 2 to have a higherdopant concentration than Layer 1, and so on. For example, each layermay be doped in a separate doping step, and/or some layers may be formedover multiple steps that at least partially overlap (e.g., such thatsome layers have higher dopant concentrations than other layers). Itshould be appreciated that, in some embodiments, layers ofphotodetection region PPD may be formed without photoresist-definedboundaries, such that the delineation between layers may be inferred bygradual rather than abrupt differences in dopant concentration.

V. Simulation Results

Some exemplary simulation results of pixels incorporating techniquesdescribed herein are presented below. It should be appreciated that thepixel configurations (e.g., doping concentrations) and simulated resultsfor the exemplary pixels presented herein are not intended to belimiting, but rather to generally demonstrate the effectiveness of thetechniques described herein in the context of a few exemplary pixels.

FIG. 3-1 is a perspective view of an exemplary pixel 3-112 that may beincluded in the integrated device 1-102, showing dopant concentrationwithin the pixel 3-112, according to some embodiments. In someembodiments, pixel 3-112 may be configured in the manner describedherein for pixel 2-112 and/or any other pixel described herein. Forinstance, in FIG. 3-1, pixel 3-112 includes photodetection region PPD,transfer gates ST0, TX0, REJ, and RS, and C/B regions, of which regionsC/B₁ and C/B₄ are shown in FIG. 3-1. In FIG. 3-1, photodetection regionPPD includes a first sub-region extending, in the first direction Dir1,from first ends of regions C/B₁ and C/B₄ past second ends of regionsC/B₁ and C/B₄, and a second sub-region extending, in the first directionDir1, from the first sub-region to drain region D and the transfergates.

FIG. 3-2 is a side view of a cross-section of the pixel 3-112 showingdopant concentration within the pixel 3-112, according to someembodiments. FIG. 3-2 also indicates two sub-cross-sections of pixel3-112 along the first direction Dir1, Slice1 and Slice2. Slice1 cutsthrough photodetection region PPD in the first direction Dir1. Slice2cuts through region C/B₄ in the first direction Dir1. FIG. 3-3 is agraph 3-300 of total dopant concentration and n-type dopantconcentration versus depth X in Slice1 of pixel 3-112 shown in FIG. 3-2,according to some embodiments. FIG. 3-4 is a graph 3-400 of p-typedopant concentration versus depth X in Slice2 of pixel 3-112 shown inFIG. 3-2, according to some embodiments. FIG. 3-2 also shows a regionC/B₆ positioned, in the first direction Dir1, before photodetectionregion PPD. It should be appreciated that any pixels described hereinmay also include region C/B₆. In some embodiments, region C/B₆ mayinclude a charge layer within an oxide layer. In FIG. 3-2, region C/B₆is optically transparent. In some embodiments, region C/B₆ may not becompletely optically transparent, as some optical loss and/or reflectionmay occur at region C/B₆.

As shown in FIGS. 3-2 and 3-3, photodetection region PPD extends, in thefirst direction Dir1, from X=6 microns to X=0 microns and regions C/B₅and C/B₄ extend alongside photodetection region PPD, in the firstdirection Dir1, from X=6 microns to X=2 microns. The first sub-regionextends, in the first direction Dir1, from X=6 microns to X=2.5 microns,and the second sub-region extends, in the first direction Dir1, fromX=2.5 microns to X=0 microns. Drain gate REJ is positioned, in the firstdirection Dir1, after X=0 microns. It should be appreciated that, insome embodiments, the first sub-region may extend, in the firstdirection Dir1, from X=6 microns to X=2 microns, and the secondsub-region may extend, in the first direction Dir1, from X=2 microns toX=0 microns.

As shown in FIG. 3-2, photodetection region PPD has multiple layers 1-5having different dopant concentrations, with the dopant concentrationsof the layers increasing from layer to layer in the first directionDir1. For instance, layer 1 has a higher dopant concentration than layer2, layer 2 has a higher dopant concentration than layer 3, layer 3 has ahigher dopant concentration than layer 4, and layer 4 has a higherdopant concentration than layer 5. In FIG. 3-2, layers 3-5 are in thesecond sub-region of photodetection region PPD, and layers 1-2 are inthe first and second sub-regions. In FIGS. 3-2 and 3-3, the dopantconcentration of photodetection region PPD along Slice1 decreases from1.3×10¹⁸ total dopants per cm³ (1.1×10¹⁷ n-type dopants per cm³) to1.6×10¹⁴ total dopants per cm³ (0.9×10¹³ n-type dopants per cm³) betweenX=0.1 microns and X=4 microns. In some embodiments, the n-type dopantsused may be arsenic. It should be appreciated that dopant concentrationsdescribed herein are exemplary and may vary according to the particularembodiment. For example, a larger pixel may be configured with a lowerdopant concentration to obtain a charge carrier depletion as describedherein at a particular bias voltage, whereas smaller pixels may beconfigured with higher dopant concentrations.

As shown in FIG. 3-4, the p-type dopant concentration along Slice2 ishighest at X=0.6 microns, reaching about 3×10²⁰ dopants per cm³. Thedopant concentration along Slice2 is lower than 10¹⁴ dopants per cm³between X=2 microns and X=6 microns proximate region C/B₄. In someembodiments, the high p-type dopant concentration along Slice2 mayisolate photodetection region PPD of pixel 3-112 from adjacent pixels.In some embodiments, the p-type dopants used may be boron.

FIG. 3-5A is a side view of a cross-section of pixel 3-112 showingcharge carrier density within the pixel 3-112, according to someembodiments. Although region C/B₆ is not shown in FIG. 3-5A, region C/B₆is still included in pixel 3-112. FIG. 3-5B is a side view of across-section of another pixel 3-112′ showing charge carrier densitywithin the pixel, according to some embodiments. Pixel 3-112′ may beconfigured in the manner described herein for pixel 3-112, except thatpixel 3-112′ does not include C/B regions (although outlines of the C/Bregions are shown in FIG. 3-5B, the illustrated regions are not chargedor biased). FIGS. 3-5A and 3-5B each show the respective pixels 3-112and 3-112′ hundreds of nanoseconds after control signals have beenapplied to transfer gate REJ, thereby inducing at least a partial chargecarrier depletion in at least part of the second sub-region ofphotodetection region PPD in each pixel.

As shown in FIG. 3-5A, photodetection region PPD of pixel 3-112 hasfewer than 5×10³ charge carriers per cm³. For instance, photodetectionregion PPD of pixel 3-112 has fewer than 2×10⁻⁶ charge carriers per cm³in the first sub-region, including fewer than 8×10⁻¹⁴ charge carriersper cm³ between X=5 microns and X=6 microns. In contrast, in FIG. 3-5B,photodetection region PPD of pixel 3-112′ has greater than 1.5×10¹²charge carriers per cm³ in photodetection region PPD, including greaterthan 10¹⁴ charge carriers per cm³ throughout the portion of the firstsub-region from X=3.7 microns to X=6 microns.

FIG. 3-6A is a graph 3-600 a showing a number of charge carriers atdifferent depths of pixels 3-112 and 3-112′ over time, according to someembodiments. FIG. 3-6B is a magnified view of a portion 3-600 b of thegraph of FIGS. 3-6A, according to some embodiments. While some portionsof FIGS. 3-6A to 3-6B purport to show fractions of a charge carrier in aregion of photodetection region PPD, it should be appreciated thatfractions of a charge carrier shown in the figures represent quantummechanical probabilities of the presence of a charge carrier that areless than 1.

As shown in FIGS. 3-6A and 3-6B, pixel 3-112 has fewer than 10 chargecarriers in the first sub-region and 8.25x10 ³ charge carriers in thesecond sub-region at time 0, and pixel 3-112′ has 1.15×10⁴ chargecarriers in the first sub-region and 9×10³ charge carriers in the secondsub-region at time 0. For instance, at time 0, substantially all of thecharge carriers in the second sub-region of the photodetection regionPPD of each pixel may be generated in response to incident photons, andsubstantially all of the charge carriers in the first sub-region of eachpixel may be free charge carriers. In FIGS. 3-6A and 3-6B, pixel 3-112has a same order of magnitude of charge carriers in the secondsub-region as pixel 3-112′, but pixel 3-112 has 4 orders of magnitudefewer charge carriers in the first sub-region than pixel 3-112′.

After 10⁻⁸ seconds, pixel 3-112 has 10⁻¹³ charge carriers in the firstsub-region and fewer than 0.5×10³ charge carriers in the secondsub-region, and pixel 3-112′ has 9.5×10³ charge carriers in the firstsub-region and 10³ charge carriers in the second sub-region. Forinstance, after 10⁻⁸ seconds, many charge carriers may have beentransferred from photodetection region PPD to the drain region D and/orto charge storage regions. Since pixel 3-112 has fewer charge carriersin the first sub-region at time 0, charge carriers are transferredfaster and more efficiently to drain and charge storage regions in pixel3-112 than in pixel 3-112′, leaving even fewer charge carriers in pixel3-112 over time than in pixel 3-112′. Moreover, since pixel 3-112′ hasmany more free charge carriers in the first sub-region at time 0, thefree charge carriers may be transferred to charge storage regions asnoise that pollutes the number of charge carriers generated in responseto incident photons. Moreover, in some applications, excitation chargecarriers generated in response to an excitation pulse may need to betransferred to the drain region within 1 nanosecond of the excitationpulse in order for fluorescence charge carriers generated following theexcitation pulse to be quickly and efficiently transferred to the chargestorage regions. Thus, pixel 3-112′ may not be suitable for suchapplications because many excitation charge carriers remain in the pixelafter 1 nanosecond has passed. It should be appreciated that the numberof charge carriers at any given time within pixels described herein mayvary according to the pixel configuration, mode of operation, andoperating environment.

FIG. 3-7A is a side view of a cross-section of pixel 3-112 showingelectric fields within the pixel 3-112, according to some embodiments.FIG. 3-7B is a side view of a cross-section of pixel 3-112′ showingelectric fields within the pixel 3-112′, according to some embodiments.FIG. 3-8 is a graph 3-800 of electric field versus depth X forsub-cross-sections Slicel and Slice1′ of pixels 3-112 and 3-112′,respectively, according to some embodiments.

As shown in FIGS. 3-7A and 3-7B, the photodetection regions PPD ofpixels 3-112 and 3-112′ have an electrical field between 4×10⁴ V/cm and4×10⁵ V/cm between X=0 microns and X=0.1 microns as well as in the draintransfer channels between the photodetection regions PPD and drainregions D. In the sub-cross-sections represented in FIG. 3-8, each pixelhas an electric field of 1.1×10⁵ between X=0 microns and X=0.2 microns.In FIGS. 3-7A and 3-7B, pixel 3-112 has an electric field greater than1.2×10⁴ in photodetection region PPD at regions C/B₅ and C/B₄ from X=6microns to X=2 microns, whereas pixel 3-112′ has an electric field lessthan 1.2×10⁻² V/cm between X=6 microns and X=3.6 microns. Slice1 ofpixel 3-112 represented in FIG. 3-8 has an electric field greater than1.1×10³ V/cm from X=0.5 microns to X=6 microns, including greater than10⁴ at X=6 microns. Slice1′ of pixel 3-112′ represented in FIG. 3-8 hasan electric field lower than 1.3×10³ V/cm from X=0.5 microns to X=6microns, including lower than 10³ V/cm from X=3 microns to X=6 microns,and lower than 10² V/cm from X=3.6 microns to X=6 microns. The electricfields shown in photodetection region PPD of pixel 3-112 at regions C/B₅and C/B₄ may deplete at least the first sub-region of photodetectionregion PPD of charge carriers, such as shown in FIG. 3-5A.

FIG. 3-9A is a graph 3-900 a showing a number of charge carriers atdifferent depths and in total within photodetection region PPD of pixel3-112 over time, according to some embodiments. FIG. 3-9B is a magnifiedview of a portion 3-900 b of the graph of FIG. 3-9A, according to someembodiments. FIG. 3-9C is a further magnified view of a portion 3-900 cof the graph of FIG. 3-9B, according to some embodiments. In FIGS. 3-9Ato 3-9C, the number of charge carriers is shown for the first and secondsub-regions of photodetection region PPD and in total for photodetectionregion PPD. While some portions of FIGS. 3-9A to 3-9C purport to showfractions of a charge carrier in a region of photodetection region PPD,it should be appreciated that fractions of a charge carrier shown in thefigures represent quantum mechanical probabilities of the presence of acharge carrier that are less than 1. As shown in FIGS. 3-9A to 3-9C,photodetection region PPD of pixel 3-112 has 0 charge carriers in totalat time 0.

In some embodiments, during operation of pixel 3-112, charge carriersreceived at the first sub-region may be transferred to the drain regionor charge storage region via the second sub-region of photodetectionregion PPD. At time 0.5×10⁻¹⁰ seconds, photodetection region PPD has 0.8total charge carriers, with 0.75 charge carriers in the first sub-regionand 0.05 charge carriers in the second sub-region. At time 3.2×10⁻¹⁰seconds, photodetection region PPD has 0.4 total charge carriers, with0.2 charge carriers in each of the first and second sub-regions. After1.3×10⁻⁹ seconds, the total number of charge carriers in photodetectionregion PPD asymptotically approaches 10⁻⁴, with more than an order ofmagnitude fewer charge carriers in the first sub-region than in thesecond sub-region after 1.5×10⁻⁹ seconds. After 10⁻⁸ seconds, the ratioof charge carriers in the second sub-region versus in the firstsub-region is greater than 8,000.

FIG. 3-10 is a graph 3-1000 showing a number of charge carriers overtime for multiple pixels having different configurations, according tosome embodiments. FIG. 3-10 shows a number of charge carriers of pixelshaving thicknesses of 3 microns, 4.5 microns, and 6 microns, in thefirst direction Dir1. For each thickness, the number of charge carriersis shown for a backside illuminated (BSI) pixel and a front-sideilluminated (FSI) pixel having the given thickness. As described herein,a BSI pixel may be configured to receive incident photons in the firstdirection Dir1, and the charge storage regions and transfer gates of theBSI pixel may be positioned on an opposite side of the BSI pixel, in thefirst direction Dir1, from where incident photons are received. An FSIpixel may be configured to receive incident photons in the firstdirection Dir1, with the charge storage regions and transfer gatespositioned on the same side of the FSI pixel, in the first directionDir1, as where incident photons are received. As shown in FIG. 3-10,pixels having smaller thicknesses have fewer charge carriers, as smallerpixels have fewer free charge carriers by virtue of their smaller size.Also shown in FIG. 3-10, for FSI pixels and BSI pixels having the samethicknesses, FSI pixels have fewer charge carriers at least in part dueto the charge storage regions and transfer gates of the FSI pixel beingpositioned at the side of the pixel that receives the incident photons,such that the charge carriers generated in the FSI pixel have a shortertravel distance to reach the charge storage regions.

FIG. 3-11A is a side view of a cross-section of a pixel 3-112, having adepth X of 6 microns, showing charge carrier density of the pixel 1nanosecond after an excitation pulse, according to some embodiments.FIG. 3-11B is a side view of a cross-section of a pixel 3-112″, having adepth X of 4.5 microns, showing charge carriers within the pixel 3-112″1 nanosecond after an excitation pulse, according to some embodiments.Pixel 3-112″ may be configured in the manner described herein for pixel3-112, except for the difference in depth X.

1 nanosecond after an excitation pulse, pixel 3-112 may be transferringcharge carriers generated in response to the excitation or resultingfluorescence emissions to the drain region or charge storage regions. Asshown in FIG. 3-11A, some portions of photodetection region PPD of pixel3-112 have greater than 1×10⁸ charge carriers per cm³, and substantiallyall of photodetection region PPD between X=6 microns and X=3.4 micronshas greater than 30 charge carrier per cm³. In contrast, after 1nanosecond, pixel 3-112″ may have transferred substantially all of thegenerated charge carriers to the drain or charge storage regions. InFIG. 3-11B, pixel 3-112″ has fewer than 2 charge carriers per cm³ fromX=1.5 microns to X=4.5 microns. Because pixel 3-112″ has a smaller depthX than pixel 3-112, pixel 3-112″ has fewer free charge carriers and mayhave stronger electric fields that cause the transfer of charge carrierswithin photodetection region PPD to be faster and more efficient than inpixel 3-112.

FIG. 3-12A is a side view of the cross-section of pixel 3-112 showingelectric fields within the pixel 3-112, according to some embodiments.FIG. 3-12B is a side view of the cross-section of pixel 3-112″ showingelectric fields within the pixel 3-112″, according to some embodiments.FIG. 3-12B indicates a sub-cross-section Slice1″ of pixel 3-112. FIG.3-13 is a graph 3-1300 of electric field versus depth X for Slice1 ofpixel 3-112 and Slice2 of pixel 3-112″, respectively, according to someembodiments. As shown in FIGS. 3-12A, 3-12B, and 3-13, pixels 3-112 and3-112″ have substantially equal electric fields throughout the secondsub-region in pixel 3-112 from X=0 microns to X=2.5 microns(corresponding to the second sub-region and much of the first sub-regionof pixel 3-112″). In the first sub-region of pixel 3-112, between X=2.6microns and X=4.5 microns, the electric fields in Slicel of pixel 3-112decrease to below 10³ V/cm, whereas the electric fields in Slice1″ ofpixel 3-112″ only decrease to 1.2×10³ V/cm before increasing above 10⁴V/cm. The electric fields in Slice1 of pixel 3-112 increase above 10⁴V/cm closer to X=6 microns. As a result of the smaller depth of pixel3-112″, the electric fields of pixel 3-112″ do not dip as low as theelectric fields of pixel 3-112 at depths greater than X=2.6 microns,thereby increasing the rate of charge transfer in pixel 3-112″ ascompared to pixel 3-112.

VI. Optical Rejection Techniques

The inventors have also developed techniques to direct, refract, and/orreflect incident photons and/or charge carriers toward thephotodetection region of a pixel and/or away from the charge storageregion(s) of the pixel. By directing, refracting, and/or reflectingphotons and/or charge carriers toward the photodetection region, fewerincident photons and/or charge carriers may reach undesired portions ofthe pixel and/or adjacent pixels, such as charge storage regions, wherethe charge carriers and/or photons may add noise to the charge storageregions. Similarly, by directing, refracting, and/or reflecting incidentphotons and/or charge carriers away from the charge storage region(s) ofthe pixel, fewer noise photons and/or charge carriers may add noise tothe charge storage region(s) of the pixel. In some embodiments, C/Bregions of a pixel may be further configured to prevent incident photonsand/or charge carriers from leaving the photodetection region and/orreaching the charge storage regions by paths other than via transfergates, as described herein.

FIG. 4-1 is a side view of a cross-section of a pixel 4-112incorporating optical rejection techniques that may be included in theintegrated device 1-102, according to some embodiments. In someembodiments, pixel 4-112 may be configured in the manner describedherein for any of pixels 1-112, 2-112, and 3-112. For instance, as shownin FIG. 4-1, pixel 4-112 includes photodetection region PPD, chargestorage region SD0, and transfer gate ST0.

In some embodiments, pixel 4-112 may include one or more barriers. Asshown in FIG. 4-1, pixel 4-112 includes a region C/B_(a) positioned at afirst end of photodetection region PPD and elongated parallel to thefirst direction Dir1. In some embodiments, region C/B_(a) may beconfigured to block charge carriers. For example, in some embodiments,the first barrier region C/B_(a) may be configured to block chargecarriers in photodetection region PPD from reaching other portions ofintegrated device 1-102, such that the charge carriers may betransferred to drain region D or charge storage region SD0 asappropriate (e.g., depending on arrival time). In some embodiments,region C/B_(a) may include a dielectric material (e.g., an oxide layerand/or oxide compound) with a charge layer. In some embodiments, abarrier including a doped region having an opposite conductivity typefrom photodetection region PPD and charge storage region SD0 may bedisposed around at least a portion of region C/B_(a). By blocking chargecarriers at region C/B_(a), pixel 4-112 may be configured to generateand transfer charge carriers to drain region D and/or charge storageregion SD0 at a higher rate and with greater efficiency.

Also shown in FIG. 4-1, pixel 4-112 includes region C/B_(b) positionedbefore charge storage region SD0 in the first direction Dir1. In someembodiments, region C/B_(b) may be configured to block charge carriersfrom reaching charge storage region SD0. For example, in someembodiments, region C/B_(b) may be configured to block charge carriersin photodetection region PPD or elsewhere in pixel 4-112 or integrateddevice 1-102 from reaching charge storage region SD0. In someembodiments, region C/B_(b) may include a dielectric material and/or adoped region having a dopant concentration opposite that ofphotodetection region PPD and charge storage region SD0. By blockingcharge carriers from reaching charge storage region SD0, fewer noisecharge carriers may reach or be generated in charge storage region SD0,increasing the signal to noise ratio of charge carriers stored in chargestorage region SD0.

Also shown in FIG. 4-1, pixel 4-112 includes a first metal layerpositioned before region C/B_(a) in the first direction Dir1 and asecond metal layer positioned before region C/B_(b) in the firstdirection Dir1. In some embodiments, the first layer may be configuredto block incident photons from entering the interior of region C/B_(a).In some embodiments, the second metal layer may be configured to blockincident photons from entering the interior of region C/B_(b) and/orfrom reaching charge storage region SD0.

FIG. 4-2 is a side view of a cross-section of an alternative pixel 4-212incorporating optical rejection techniques that may be included in theintegrated device 1-102, according to some embodiments. In someembodiments, pixel 4-212 may be configured in the manner describedherein for pixel 4-112. In some embodiments, pixel 4-212 may include oneor more metal barriers configured to block incident photons and/orcharge carriers. In FIG. 4-2, pixel 4-212 includes a first metal barrierpositioned at the first end of photodetection region PPD and elongatedin the first direction Dir1. In some embodiments, the first metalbarrier may be configured to reflect photons and/or charge carriersincident on the first metal barrier, such that the incident photonsand/or charge carriers remain in photodetection region PPD. In someembodiments, the first metal barrier may be configured to induce acharge carrier depletion in photodetection region PPD and/or aphotodetection region PPD of an adjacent pixel. For example, the firstmetal barrier may be configured to receive a voltage bias that inducesthe charge carrier depletion in the photodetection region PPD and/or aphotodetection region of an adjacent pixel.

Also shown in FIG. 4-2, pixel 4-212 includes second metal barrierspositioned at first and second ends of charge storage region SD0 andelongated in the first direction Dir1. In some embodiments, the secondmetal barriers may be configured to reflect photons and/or chargecarriers incident on charge storage region SD0. In some embodiments, oneor each second metal barrier may be configured to induce a chargecarrier depletion in the photodetection region PPD of pixel 4-212 and/orof an adjacent pixel. In FIG. 4-2, the two second metal barriers areconnected by a metal layer that may be configured in the mannerdescribed herein for the metal layer positioned, in the first directionDir1, after the second barrier BPW in FIG. 4-1.

FIG. 4-3 is a side view of a cross-section of a further alternativepixel 4-312 incorporating optical rejection techniques that may beincluded in the integrated device 1-102, according to some embodiments.In some embodiments, pixel 4-312 may be configured in the mannerdescribed herein for pixel 4-212. In FIG. 4-3, photodetection region PPDof pixel 4-312 includes multiple layers, PD1 and PD2, with layer PD1spaced from layer PD2 in the first direction Dir1. In some embodiments,layers PD1 and PD2 may have different intrinsic electric potentiallevels. For example, layer PD1 may have a higher dopant concentrationthan layer PD2.

In some embodiments, pixel 4-312 may also include an optically directivestructure configured to direct incident photons toward photodetectionregion PPD. For example, the optically directive structure may beconfigured to refract photons incident on pixel 4-312 in obliquedirections with respect to the first direction Dir 1. In FIG. 4-3, pixel4-312 includes an optically directive structure at a surface that ispositioned before photodetection region PPD in the first direction Dir1,the optically directive structure including a plurality of openingspositioned along the surface. In some embodiments, the openings mayinclude a dielectric material such as air and/or oxide.

In FIG. 4-3, pixel 4-312 also includes regions C/B_(a) and C/B_(b),which may be configured in the manner described herein for the C/Bregions shown in FIG. 4-1, including metal layers positioned before theC/B regions in the first direction Dir1.

VII. DNA and/or RNA Sequencing Applications

An analytic system described herein may include an integrated device andan instrument configured to interface with the integrated device. Theintegrated device may include an array of pixels, where a pixel includesa reaction chamber and at least one photodetector. A surface of theintegrated device may have a plurality of reaction chambers, where areaction chamber is configured to receive a sample from a suspensionplaced on the surface of the integrated device. A suspension may containmultiple samples of a same type, and in some embodiments, differenttypes of samples. In this regard, the phrase “sample of interest” asused herein can refer to a plurality of samples of a same type that aredispersed in a suspension, for example. Similarly, the phrase “moleculeof interest” as used herein can refer to a plurality of molecules of asame type that are dispersed in a suspension. The plurality of reactionchambers may have a suitable size and shape such that at least a portionof the reaction chambers receive one sample from a suspension. In someembodiments, the number of samples within a reaction chamber may bedistributed among the reaction chambers such that some reaction chamberscontain one sample with others contain zero, two or more samples.

In some embodiments, a suspension may contain multiple single-strandedDNA templates, and individual reaction chambers on a surface of anintegrated device may be sized and shaped to receive a sequencingtemplate. Sequencing templates may be distributed among the reactionchambers of the integrated device such that at least a portion of thereaction chambers of the integrated device contain a sequencingtemplate. The suspension may also contain labeled nucleotides which thenenter in the reaction chamber and may allow for identification of anucleotide as it is incorporated into a strand of DNA complementary tothe single-stranded DNA template in the reaction chamber. In someembodiments, the suspension may contain sequencing templates and labelednucleotides may be subsequently introduced to a reaction chamber asnucleotides are incorporated into a complementary strand within thereaction chamber. In this manner, timing of incorporation of nucleotidesmay be controlled by when labeled nucleotides are introduced to thereaction chambers of an integrated device.

Excitation light is provided from an excitation source located separatefrom the pixel array of the integrated device. The excitation light isdirected at least in part by elements of the integrated device towardsone or more pixels to illuminate an illumination region within thereaction chamber. A marker may then emit emission light when locatedwithin the illumination region and in response to being illuminated byexcitation light. In some embodiments, one or more excitation sourcesare part of the instrument of the system where components of theinstrument and the integrated device are configured to direct theexcitation light towards one or more pixels.

Emission light emitted from a reaction chamber (e.g., by a fluorescentlabel) may then be detected by one or more photodetectors within a pixelof the integrated device. Characteristics of the detected emission lightmay provide an indication for identifying the marker associated with theemission light. Such characteristics may include any suitable type ofcharacteristic, including an arrival time of photons detected by aphotodetector, an amount of photons accumulated over time by aphotodetector, and/or a distribution of photons across two or morephotodetectors. In some embodiments, a photodetector may have aconfiguration that allows for the detection of one or more timingcharacteristics associated with emission light (e.g., fluorescencelifetime). The photodetector may detect a distribution of photon arrivaltimes after a pulse of excitation light propagates through theintegrated device, and the distribution of arrival times may provide anindication of a timing characteristic of the emission light (e.g., aproxy for fluorescence lifetime). In some embodiments, the one or morephotodetectors provide an indication of the probability of emissionlight emitted by the marker (e.g., fluorescence intensity). In someembodiments, a plurality of photodetectors may be sized and arranged tocapture a spatial distribution of the emission light. Output signalsfrom the one or more photodetectors may then be used to distinguish amarker from among a plurality of markers, where the plurality of markersmay be used to identify a sample or its structure. In some embodiments,a sample may be excited by multiple excitation energies, and emissionlight and/or timing characteristics of the emission light from thereaction chamber in response to the multiple excitation energies maydistinguish a marker from a plurality of markers.

A schematic overview of the system 5-100 is illustrated in FIG. 5-1A.The system comprises an integrated device 5-102 that interfaces with aninstrument 5-104. It should be appreciated that any or all integrateddevices described herein may be used in place or of or in addition tointegrated device 5-102. In some embodiments, instrument 5-104 mayinclude one or more excitation sources 5-106 integrated as part ofinstrument 5-104. In some embodiments, an excitation source may beexternal to both instrument 5-104 and integrated device 5-102, andinstrument 5-104 may be configured to receive excitation light from theexcitation source and direct excitation light to the integrated device.The integrated device may interface with the instrument using anysuitable socket for receiving the integrated device and holding it inprecise optical alignment with the excitation source. The excitationsource 5-106 may be configured to provide excitation light to theintegrated device 5-102. As illustrated schematically in FIG. 5-1A, theintegrated device 5-102 has a plurality of pixels 5-112, where at leasta portion of pixels may perform independent analysis of a sample ofinterest. Such pixels 5-112 may be referred to as “passive sourcepixels” since a pixel receives excitation light from a source 5-106separate from the pixel, where excitation light from the source excitessome or all of the pixels 5-112. Excitation source 5-106 may be anysuitable light source. Examples of suitable excitation sources aredescribed in U.S. patent application Ser. No. 14/821,688, filed Aug. 7,2015, titled “INTEGRATED DEVICE FOR PROBING, DETECTING AND ANALYZINGMOLECULES,” which is incorporated by reference in its entirety. In someembodiments, excitation source 5-106 includes multiple excitationsources that are combined to deliver excitation light to integrateddevice 5-102. The multiple excitation sources may be configured toproduce multiple excitation energies or wavelengths.

A pixel 5-112 has a reaction chamber 5-108 configured to receive asingle sample of interest and a photodetector 5-110 for detectingemission light emitted from the reaction chamber in response toilluminating the sample and at least a portion of the reaction chamber5-108 with excitation light provided by the excitation source 5-106. Insome embodiments, reaction chamber 5-108 may retain the sample inproximity to a surface of integrated device 5-102, which may easedelivery of excitation light to the sample and detection of emissionlight from the sample or a reaction component (e.g., a labelednucleotide).

Optical elements for coupling excitation light from excitation lightsource 5-106 to integrated device 5-102 and guiding excitation light tothe reaction chamber 5-108 are located both on integrated device 5-102and the instrument 5-104. Source-to-chamber optical elements maycomprise one or more grating couplers located on integrated device 5-102to couple excitation light to the integrated device and waveguides todeliver excitation light from instrument 5-104 to reaction chambers inpixels 5-112. One or more optical splitter elements may be positionedbetween a grating coupler and the waveguides. The optical splitter maycouple excitation light from the grating coupler and deliver excitationlight to at least one of the waveguides. In some embodiments, theoptical splitter may have a configuration that allows for delivery ofexcitation light to be substantially uniform across all the waveguidessuch that each of the waveguides receives a substantially similar amountof excitation light. Such embodiments may improve performance of theintegrated device by improving the uniformity of excitation lightreceived by reaction chambers of the integrated device.

Reaction chamber 5-108, a portion of the excitation source-to-chamberoptics, and the reaction chamber-to-photodetector optics are located onintegrated device 5-102. Excitation source 5-106 and a portion of thesource-to-chamber components are located in instrument 5-104. In someembodiments, a single component may play a role in both couplingexcitation light to reaction chamber 5-108 and delivering emission lightfrom reaction chamber 5-108 to photodetector 5-110. Examples of suitablecomponents, for coupling excitation light to a reaction chamber and/ordirecting emission light to a photodetector, to include in an integrateddevice are described in U.S. patent application Ser. No. 14/821,688,filed Aug. 7, 2015, titled “INTEGRATED DEVICE FOR PROBING, DETECTING ANDANALYZING MOLECULES,” and U.S. patent application Ser. No. 14/543,865,filed Nov. 17, 2014, titled “INTEGRATED DEVICE WITH EXTERNAL LIGHTSOURCE FOR PROBING, DETECTING, AND ANALYZING MOLECULES,” both of whichare incorporated by reference in their entirety.

Pixel 5-112 is associated with its own individual reaction chamber 5-108and at least one photodetector 5-110. The plurality of pixels ofintegrated device 5-102 may be arranged to have any suitable shape,size, and/or dimensions. Integrated device 5-102 may have any suitablenumber of pixels. The number of pixels in integrated device 5-102 may bein the range of approximately 10,000 pixels to 1,000,000 pixels or anyvalue or range of values within that range. In some embodiments, thepixels may be arranged in an array of 512 pixels by 512 pixels.Integrated device 5-102 may interface with instrument 5-104 in anysuitable manner. In some embodiments, instrument 5-104 may have aninterface that detachably couples to integrated device 5-102 such that auser may attach integrated device 5-102 to instrument 5-104 for use ofintegrated device 5-102 to analyze at least one sample of interest in asuspension and remove integrated device 5-102 from instrument 5-104 toallow for another integrated device to be attached. The interface ofinstrument 5-104 may position integrated device 5-102 to couple withcircuitry of instrument 5-104 to allow for readout signals from one ormore photodetectors to be transmitted to instrument 5-104. Integrateddevice 5-102 and instrument 5-104 may include multi-channel, high-speedcommunication links for handling data associated with large pixel arrays(e.g., more than 10,000 pixels).

A cross-sectional schematic of integrated device 5-102 illustrating arow of pixels 5-112 is shown in FIG. 5-1B. Integrated device 5-102 mayinclude coupling region 5-201, routing region 5-202, and pixel region5-203. Pixel region 5-203 may include a plurality of pixels 5-112 havingreaction chambers 5-108 positioned on a surface at a location separatefrom coupling region 5-201, which is where excitation light (shown asthe dashed arrow) couples to integrated device 5-102. Reaction chambers5-108 may be formed through metal layer(s) 5-116. One pixel 5-112,illustrated by the dotted rectangle, is a region of integrated device5-102 that includes a reaction chamber 5-108 and a photodetection regionhaving one or more photodetectors 5-110.

FIG. 5-1B illustrates the path of excitation (shown in dashed lines) bycoupling a beam of excitation light to coupling region 5-201 and toreaction chambers 5-108. The row of reaction chambers 5-108 shown inFIG. 5-1B may be positioned to optically couple with waveguide 5-220.Excitation light may illuminate a sample located within a reactionchamber. The sample or a reaction component (e.g., fluorescent label)may reach an excited state in response to being illuminated by theexcitation light. When in an excited state, the sample or reactioncomponent may emit emission light, which may be detected by one or morephotodetectors associated with the reaction chamber. FIG. 5-1Bschematically illustrates the path of emission light (shown as the solidline) from a reaction chamber 5-108 to photodetector(s) 5-110 of pixel5-112. The photodetector(s) 5-110 of pixel 5-112 may be configured andpositioned to detect emission light from reaction chamber 5-108.Examples of suitable photodetectors are described in U.S. patentapplication Ser. No. 14/821,656, filed Aug. 7, 2015, titled “INTEGRATEDDEVICE FOR TEMPORAL BINNING OF RECEIVED PHOTONS,” which is incorporatedby reference in its entirety. For an individual pixel 5-112, a reactionchamber 5-108 and its respective photodetector(s) 5-110 may be alignedalong a common axis (along the y-direction shown in FIG. 5-1B). In thismanner, the photodetector(s) may overlap with the reaction chamberwithin a pixel 5-112.

The directionality of the emission light from a reaction chamber 5-108may depend on the positioning of the sample in the reaction chamber5-108 relative to metal layer(s) 5-116 because metal layer(s) 5-116 mayact to reflect emission light. In this manner, a distance between metallayer(s) 5-116 and a fluorescent marker positioned in a reaction chamber5-108 may impact the efficiency of photodetector(s) 5-110, that are inthe same pixel as the reaction chamber, to detect the light emitted bythe fluorescent marker. The distance between metal layer(s) 5-116 andthe bottom surface of a reaction chamber 5-108, which is proximate towhere a sample may be positioned during operation, may be in the rangeof 100 nm to 500 nm, or any value or range of values in that range. Insome embodiments the distance between metal layer(s) 5-116 and thebottom surface of a reaction chamber 5-108 is approximately 300 nm.

The distance between the sample and the photodetector(s) may also impactefficiency in detecting emission light. By decreasing the distance lighthas to travel between the sample and the photodetector(s), detectionefficiency of emission light may be improved. In addition, smallerdistances between the sample and the photodetector(s) may allow forpixels that occupy a smaller area footprint of the integrated device,which can allow for a higher number of pixels to be included in theintegrated device. The distance between the bottom surface of a reactionchamber 5-108 and photodetector(s) may be in the range of 1 μm to 15 μm,or any value or range of values in that range.

Photonic structure(s) 5-230 may be positioned between reaction chambers5-108 and photodetectors 5-110 and configured to reduce or preventexcitation light from reaching photodetectors 5-110, which may otherwisecontribute to signal noise in detecting emission light. As shown in FIG.5-1B, the one or more photonic structures 5-230 may be positionedbetween waveguide 5-220 and photodetectors 5-110. Photonic structure(s)5-230 may include one or more optical rejection photonic structuresincluding a spectral filter, a polarization filter, and a spatialfilter. Photonic structure(s) 5-230 may be positioned to align withindividual reaction chambers 5-108 and their respective photodetector(s)5-110 along a common axis. Metal layers 5-240, which may act as acircuitry for integrated device 5-102, may also act as a spatial filter,in accordance with some embodiments. In such embodiments, one or moremetal layers 5-240 may be positioned to block some or all excitationlight from reaching photodetector(s) 5-110.

Coupling region 5-201 may include one or more optical componentsconfigured to couple excitation light from an external excitationsource. Coupling region 5-201 may include grating coupler 5-216positioned to receive some or all of a beam of excitation light.Examples of suitable grating couplers are described in U.S. patentapplication Ser. No. 15/844,403, filed Dec. 15, 2017, titled “OPTICALCOUPLER AND WAVEGUIDE SYSTEM,” which is incorporated by reference in itsentirety. Grating coupler 5-216 may couple excitation light to waveguide5-220, which may be configured to propagate excitation light to theproximity of one or more reaction chambers 5-108. Alternatively,coupling region 5-201 may comprise other well-known structures forcoupling light into a waveguide.

Components located off of the integrated device may be used to positionand align the excitation source 5-106 to the integrated device. Suchcomponents may include optical components including lenses, mirrors,prisms, windows, apertures, attenuators, and/or optical fibers.Additional mechanical components may be included in the instrument toallow for control of one or more alignment components. Such mechanicalcomponents may include actuators, stepper motors, and/or knobs. Examplesof suitable excitation sources and alignment mechanisms are described inU.S. patent application Ser. No. 15/161,088, filed May 20, 2016, titled“PULSED LASER AND SYSTEM,” which is incorporated by reference in itsentirety. Another example of a beam-steering module is described in U.S.patent application Ser. No. 15/842,720, filed Dec. 14, 2017, titled“COMPACT BEAM SHAPING AND STEERING ASSEMBLY,” which is incorporatedherein by reference.

A sample to be analyzed may be introduced into reaction chamber 5-108 ofpixel 5-112. The sample may be a biological sample or any other suitablesample, such as a chemical sample. In some cases, the suspension mayinclude multiple molecules of interest and the reaction chamber may beconfigured to isolate a single molecule. In some instances, thedimensions of the reaction chamber may act to confine a single moleculewithin the reaction chamber, allowing measurements to be performed onthe single molecule. Excitation light may be delivered into the reactionchamber 5-108, so as to excite the sample or at least one fluorescentmarker attached to the sample or otherwise associated with the samplewhile it is within an illumination area within the reaction chamber5-108.

In operation, parallel analyses of samples within the reaction chambersare carried out by exciting some or all of the samples within thereaction chambers using excitation light and detecting signals with thephotodetectors that are representative of emission light from thereaction chambers. Emission light from a sample or reaction component(e.g., fluorescent label) may be detected by a correspondingphotodetector and converted to at least one electrical signal. Theelectrical signals may be transmitted along conducting lines (e.g.,metal layers 5-240) in the circuitry of the integrated device, which maybe connected to an instrument interfaced with the integrated device. Theelectrical signals may be subsequently processed and/or analyzed.Processing or analyzing of electrical signals may occur on a suitablecomputing device either located on or off the instrument.

Instrument 5-104 may include a user interface for controlling operationof instrument 5-104 and/or integrated device 5-102. The user interfacemay be configured to allow a user to input information into theinstrument, such as commands and/or settings used to control thefunctioning of the instrument. In some embodiments, the user interfacemay include buttons, switches, dials, and a microphone for voicecommands. The user interface may allow a user to receive feedback on theperformance of the instrument and/or integrated device, such as properalignment and/or information obtained by readout signals from thephotodetectors on the integrated device. In some embodiments, the userinterface may provide feedback using a speaker to provide audiblefeedback. In some embodiments, the user interface may include indicatorlights and/or a display screen for providing visual feedback to a user.

In some embodiments, instrument 5-104 may include a computer interfaceconfigured to connect with a computing device. Computer interface may bea USB interface, a FireWire interface, or any other suitable computerinterface. Computing device may be any general purpose computer, such asa laptop or desktop computer. In some embodiments, computing device maybe a server (e.g., cloud-based server) accessible over a wirelessnetwork via a suitable computer interface. The computer interface mayfacilitate communication of information between instrument 5-104 and thecomputing device. Input information for controlling and/or configuringthe instrument 5-104 may be provided to the computing device andtransmitted to instrument 5-104 via the computer interface. Outputinformation generated by instrument 5-104 may be received by thecomputing device via the computer interface. Output information mayinclude feedback about performance of instrument 5-104, performance ofintegrated device 5-102, and/or data generated from the readout signalsof photodetector 5-110.

In some embodiments, instrument 5-104 may include a processing deviceconfigured to analyze data received from one or more photodetectors ofintegrated device 5-102 and/or transmit control signals to excitationsource(s) 5-106. In some embodiments, the processing device may comprisea general purpose processor, a specially-adapted processor (e.g., acentral processing unit (CPU) such as one or more microprocessor ormicrocontroller cores, a field-programmable gate array (FPGA), anapplication-specific integrated circuit (ASIC), a custom integratedcircuit, a digital signal processor (DSP), or a combination thereof.) Insome embodiments, the processing of data from one or more photodetectorsmay be performed by both a processing device of instrument 5-104 and anexternal computing device. In other embodiments, an external computingdevice may be omitted and processing of data from one or morephotodetectors may be performed solely by a processing device ofintegrated device 5-102.

Referring to FIG. 5-1C, a portable, advanced analytic instrument 5-100can comprise one or more pulsed optical sources 5-106 mounted as areplaceable module within, or otherwise coupled to, the instrument5-100. The portable analytic instrument 5-100 can include an opticalcoupling system 5-115 and an analytic system 5-160. The optical couplingsystem 5-115 can include some combination of optical components (whichmay include, for example, none, one from among, or more than onecomponent from among the following components: lens, mirror, opticalfilter, attenuator, beam-steering component, beam shaping component) andbe configured to operate on and/or couple output optical pulses 5-122from the pulsed optical source 5-106 to the analytic system 5-160. Theanalytic system 5-160 can include a plurality of components that arearranged to direct the optical pulses to at least one reaction chamberfor sample analysis, receive one or more optical signals (e.g.,fluorescence, backscattered radiation) from the at least one reactionchamber, and produce one or more electrical signals representative ofthe received optical signals. In some embodiments, the analytic system5-160 can include one or more photodetectors and may also includesignal-processing electronics (e.g., one or more microcontrollers, oneor more field-programmable gate arrays, one or more microprocessors, oneor more digital signal processors, logic gates, etc.) configured toprocess the electrical signals from the photodetectors. The analyticsystem 5-160 can also include data transmission hardware configured totransmit and receive data to and from external devices (e.g., one ormore external devices on a network to which the instrument 5-100 canconnect via one or more data communications links). In some embodiments,the analytic system 5-160 can be configured to receive abio-optoelectronic chip 5-140, which holds one or more samples to beanalyzed.

FIG. 5-1D depicts a further detailed example of a portable analyticalinstrument 5-100 that includes a compact pulsed optical source 5-106. Inthis example, the pulsed optical source 5-106 comprises a compact,passively mode-locked laser module 5-113. A passively mode-locked lasercan produce optical pulses autonomously, without the application of anexternal pulsed signal. In some implementations, the module can bemounted to an instrument chassis or frame 5-103, and may be locatedinside an outer casing of the instrument. According to some embodiments,a pulsed optical source 5-106 can include additional components that canbe used to operate the optical source and operate on an output beam fromthe optical source 5-106. A mode-locked laser 5-113 may comprise anelement (e.g., saturable absorber, acousto-optic modulator, Kerr lens)in a laser cavity, or coupled to the laser cavity, that induces phaselocking of the laser's longitudinal frequency modes. The laser cavitycan be defined in part by cavity end mirrors 5-111, 5-119. Such lockingof the frequency modes results in pulsed operation of the laser (e.g.,an intracavity pulse 5-120 bounces back-and-forth between the cavity endmirrors) and produces a stream of output optical pulses 5-122 from oneend mirror 5-111 which is partially transmitting.

In some cases, the analytic instrument 5-100 is configured to receive aremovable, packaged, bio-optoelectronic or optoelectronic chip 5-140(also referred to as a “disposable chip”). The disposable chip caninclude a bio-optoelectronic chip, for example, that comprises aplurality of reaction chambers, integrated optical components arrangedto deliver optical excitation energy to the reaction chambers, andintegrated photodetectors arranged to detect fluorescent emission fromthe reaction chambers. In some implementations, the chip 5-140 can bedisposable after a single use, whereas in other implementations the chip5-140 can be reused two or more times. When the chip 5-140 is receivedby the instrument 5-100, it can be in electrical and opticalcommunication with the pulsed optical source 5-106 and with apparatus inthe analytic system 5-160. Electrical communication may be made throughelectrical contacts on the chip package, for example.

In some embodiments and referring to FIG. 5-1D, the disposable chip5-140 can be mounted (e.g., via a socket connection) on an electroniccircuit board 5-130, such as a printed circuit board (PCB) that caninclude additional instrument electronics. For example, the PCB 5-130can include circuitry configured to provide electrical power, one ormore clock signals, and control signals to the optoelectronic chip5-140, and signal-processing circuitry arranged to receive signalsrepresentative of fluorescent emission detected from the reactionchambers. Data returned from the optoelectronic chip can be processed inpart or entirely by electronics on the instrument 5-100, although datamay be transmitted via a network connection to one or more remote dataprocessors, in some implementations. The PCB 5-130 can also includecircuitry configured to receive feedback signals from the chip relatingto optical coupling and power levels of the optical pulses 5-122 coupledinto waveguides of the optoelectronic chip 5-140. The feedback signalscan be provided to one or both of the pulsed optical source 5-106 andoptical system 5-115 to control one or more parameters of the outputbeam of optical pulses 5-122. In some cases, the PCB 5-130 can provideor route power to the pulsed optical source 5-106 for operating theoptical source and related circuitry in the optical source 5-106.According to some embodiments, the pulsed optical source 5-106 comprisesa compact mode-locked laser module 5-113. The mode-locked laser cancomprise a gain medium 5-105 (which can be solid-state material in someembodiments), an output coupler 5-111, and a laser-cavity end mirror5-119. The mode-locked laser's optical cavity can be bound by the outputcoupler 5-111 and end mirror 5-119. An optical axis 5-125 of the lasercavity can have one or more folds (turns) to increase the length of thelaser cavity and provide a desired pulse repetition rate. The pulserepetition rate is determined by the length of the laser cavity (e.g.,the time for an optical pulse to make a round-trip within the lasercavity).

In some embodiments, there can be additional optical elements (not shownin FIG. 5-1D) in the laser cavity for beam shaping, wavelengthselection, and/or pulse forming. In some cases, the end mirror 5-119comprises a saturable-absorber mirror (SAM) that induces passive modelocking of longitudinal cavity modes and results in pulsed operation ofthe mode-locked laser. The mode-locked laser module 5-113 can furtherinclude a pump source (e.g., a laser diode, not shown in FIG. 5-1D) forexciting the gain medium 5-105. Further details of a mode-locked lasermodule 5-113 can be found in U.S. patent application Ser. No.15/844,469, titled “Compact Mode-Locked Laser Module,” filed Dec. 15,2017, each application of which is incorporated herein by reference.

When the laser 5-113 is mode locked, an intracavity pulse 5-120 cancirculate between the end mirror 5-119 and the output coupler 5-111, anda portion of the intracavity pulse can be transmitted through the outputcoupler 5-111 as an output pulse 5-122. Accordingly, a train of outputpulses 5-122, as depicted in the graph of FIG. 5-2, can be detected atthe output coupler as the intracavity pulse 5-120 bounces back-and-forthbetween the output coupler 5-111 and end mirror 5-119 in the lasercavity.

FIG. 5-2 depicts temporal intensity profiles of the output pulses 5-122,though the illustration is not to scale. In some embodiments, the peakintensity values of the emitted pulses may be approximately equal, andthe profiles may have a Gaussian temporal profile, though other profilessuch as a sech2 profile may be possible. In some cases, the pulses maynot have symmetric temporal profiles and may have other temporal shapes.The duration of each pulse may be characterized by afull-width-half-maximum (FWHM) value, as indicated in FIG. 5-2.According to some embodiments of a mode-locked laser, ultrashort opticalpulses can have FWHM values less than 100 picoseconds (ps). In somecases, the FWHM values can be between approximately 5 ps andapproximately 30 ps.

The output pulses 5-122 can be separated by regular intervals T. Forexample, T can be determined by a round-trip travel time between theoutput coupler 5-111 and cavity end mirror 5-119. According to someembodiments, the pulse-separation interval T can be between about 1 nsand about 30 ns. In some cases, the pulse-separation interval T can bebetween about 5 ns and about 20 ns, corresponding to a laser-cavitylength (an approximate length of the optical axis 5-125 within the lasercavity) between about 0.7 meter and about 3 meters. In embodiments, thepulse-separation interval corresponds to a round trip travel time in thelaser cavity, so that a cavity length of 3 meters (round-trip distanceof 6 meters) provides a pulse-separation interval T of approximately 20ns.

According to some embodiments, a desired pulse-separation interval T andlaser-cavity length can be determined by a combination of the number ofreaction chambers on the chip 5-140, fluorescent emissioncharacteristics, and the speed of data-handling circuitry for readingdata from the optoelectronic chip 5-140. In embodiments, differentfluorophores can be distinguished by their different fluorescent decayrates or characteristic lifetimes. Accordingly, there needs to be asufficient pulse-separation interval T to collect adequate statisticsfor the selected fluorophores to distinguish between their differentdecay rates. Additionally, if the pulse-separation interval T is tooshort, the data handling circuitry cannot keep up with the large amountof data being collected by the large number of reaction chambers.Pulse-separation interval T between about 5 ns and about 20 ns issuitable for fluorophores that have decay rates up to about 2 ns and forhandling data from between about 60,000 and 10,000,000 reactionchambers.

According to some implementations, a beam-steering module 5-150 canreceive output pulses from the pulsed optical source 5-106 and isconfigured to adjust at least the position and incident angles of theoptical pulses onto an optical coupler (e.g., grating coupler) of theoptoelectronic chip 5-140. In some cases, the output pulses 5-122 fromthe pulsed optical source 5-106 can be operated on by a beam-steeringmodule 5-150 to additionally or alternatively change a beam shape and/orbeam rotation at an optical coupler on the optoelectronic chip 5-140. Insome implementations, the beam-steering module 5-150 can further providefocusing and/or polarization adjustments of the beam of output pulsesonto the optical coupler. One example of a beam-steering module isdescribed in U.S. patent application Ser. No. 15/161,088 titled “PulsedLaser and Bioanalytic System,” filed May 20, 2016, which is incorporatedherein by reference. Another example of a beam-steering module isdescribed in a separate U.S. patent application No. 62/435,679, filedDec. 16, 2016, and titled “Compact Beam Shaping and Steering Assembly,”which is incorporated herein by reference.

Referring to FIG. 5-3, the output pulses 5-122 from a pulsed opticalsource can be coupled into one or more optical waveguides 5-312 on abio-optoelectronic chip 5-140, for example. In some embodiments, theoptical pulses can be coupled to one or more waveguides via a gratingcoupler 5-310, though coupling to an end of one or more opticalwaveguides on the optoelectronic chip can be used in some embodiments.According to some embodiments, a quad detector 5-320 can be located on asemiconductor substrate 5-305 (e.g., a silicon substrate) for aiding inalignment of the beam of optical pulses 5-122 to a grating coupler5-310. The one or more waveguides 5-312 and reaction chambers orreaction chambers 5-330 can be integrated on the same semiconductorsubstrate with intervening dielectric layers (e.g., silicon dioxidelayers) between the substrate, waveguide, reaction chambers, andphotodetectors 5-322.

Each waveguide 5-312 can include a tapered portion 5-315 below thereaction chambers 5-330 to equalize optical power coupled to thereaction chambers along the waveguide. The reducing taper can force moreoptical energy outside the waveguide's core, increasing coupling to thereaction chambers and compensating for optical losses along thewaveguide, including losses for light coupling into the reactionchambers. A second grating coupler 5-317 can be located at an end ofeach waveguide to direct optical energy to an integrated photodiode5-324. The integrated photodiode can detect an amount of power coupleddown a waveguide and provide a detected signal to feedback circuitrythat controls the beam-steering module 5-150, for example.

The reaction chambers 5-330 or reaction chambers 5-330 can be alignedwith the tapered portion 5-315 of the waveguide and recessed in a tub5-340. There can be photodetectors 5-322 located on the semiconductorsubstrate 5-305 for each reaction chamber 5-330. In some embodiments, asemiconductor absorber (shown in FIG. 5-5 as an optical filter 5-530)may be located between the waveguide and a photodetector 5-322 at eachpixel. A metal coating and/or multilayer coating 5-350 can be formedaround the reaction chambers and above the waveguide to prevent opticalexcitation of fluorophores that are not in the reaction chambers (e.g.,dispersed in a solution above the reaction chambers). The metal coatingand/or multilayer coating 5-350 may be raised beyond edges of the tub5-340 to reduce absorptive losses of the optical energy in the waveguide5-312 at the input and output ends of each waveguide.

There can be a plurality of rows of waveguides, reaction chambers, andtime-binning photodetectors on the optoelectronic chip 5-140. Forexample, there can be 128 rows, each having 512 reaction chambers, for atotal of 65,536 reaction chambers in some implementations. Otherimplementations may include fewer or more reaction chambers, and mayinclude other layout configurations. Optical power from the pulsedoptical source 5-106 can be distributed to the multiple waveguides viaone or more star couplers or multi-mode interference couplers, or by anyother means, located between an optical coupler 5-310 to the chip 5-140and the plurality of waveguides 5-312.

FIG. 5-4 illustrates optical energy coupling from an optical pulse 5-122within a tapered portion 5-315 of waveguide 5-312 to a reaction chamber5-330. The drawing has been produced from an electromagnetic fieldsimulation of the optical wave that accounts for waveguide dimensions,reaction chamber dimensions, the different materials' opticalproperties, and the distance of the tapered portion 5-315 of waveguide5-312 from the reaction chamber 5-330. The waveguide can be formed fromsilicon nitride in a surrounding medium 5-410 of silicon dioxide, forexample. The waveguide, surrounding medium, and reaction chamber can beformed by microfabrication processes described in U.S. application Ser.No. 14/821,688, filed Aug. 7, 2015, titled “Integrated Device forProbing, Detecting and Analyzing Molecules.” According to someembodiments, an evanescent optical field 5-420 couples optical energytransported by the waveguide to the reaction chamber 5-330.

A non-limiting example of a biological reaction taking place in areaction chamber 5-330 is depicted in FIG. 5-5. The example depictssequential incorporation of nucleotides or nucleotide analogs into agrowing strand that is complementary to a target nucleic acid. Thesequential incorporation can take place in a reaction chamber 5-330, andcan be detected by an advanced analytic instrument to sequence DNA. Thereaction chamber can have a depth between about 150 nm and about 250 nmand a diameter between about 80 nm and about 160 nm. A metallizationlayer 5-540 (e.g., a metallization for an electrical referencepotential) can be patterned above a photodetector 5-322 to provide anaperture or iris that blocks stray light from adjacent reaction chambersand other unwanted light sources. According to some embodiments,polymerase 5-520 can be located within the reaction chamber 5-330 (e.g.,attached to a base of the chamber). The polymerase can take up a targetnucleic acid 5-510 (e.g., a portion of nucleic acid derived from DNA),and sequence a growing strand of complementary nucleic acid to produce agrowing strand of DNA 5-512. Nucleotides or nucleotide analogs labeledwith different fluorophores can be dispersed in a solution above andwithin the reaction chamber.

When a labeled nucleotide or nucleotide analog 5-610 is incorporatedinto a growing strand of complementary nucleic acid, as depicted in FIG.5-6, one or more attached fluorophores 5-630 can be repeatedly excitedby pulses of optical energy coupled into the reaction chamber 5-330 fromthe tapered portion 5-315. In some embodiments, the fluorophore orfluorophores 5-630 can be attached to one or more nucleotides ornucleotide analogs 5-610 with any suitable linker 5-620. Anincorporation event may last for a period of time up to about 100 ms.During this time, pulses of fluorescent emission resulting fromexcitation of the fluorophore(s) by pulses from the mode-locked lasercan be detected with a time-binning photodetector 5-322, for example. Insome embodiments, there can be one or more additional integratedelectronic devices 5-323 at each pixel for signal handling (e.g.,amplification, read-out, routing, signal preprocessing, etc.). Accordingto some embodiments, each pixel can include at least one optical filter5-530 (e.g., a semiconductor absorber) that passes fluorescent emissionand reduces transmission of radiation from the excitation pulse. Someimplementations may not use the optical filter 5-530. By attachingfluorophores with different emission characteristics (e.g., fluorescentdecay rates, intensity, fluorescent wavelength) to the differentnucleotides (A,C,G,T), detecting and distinguishing the differentemission characteristics while the strand of DNA 5-512 incorporates anucleic acid and enables determination of the genetic sequence of thegrowing strand of DNA.

According to some embodiments, an advanced analytic instrument 5-100that is configured to analyze samples based on fluorescent emissioncharacteristics can detect differences in fluorescent lifetimes and/orintensities between different fluorescent molecules, and/or differencesbetween lifetimes and/or intensities of the same fluorescent moleculesin different environments. By way of explanation, FIG. 5-7 plots twodifferent fluorescent emission probability curves (A and B), which canbe representative of fluorescent emission from two different fluorescentmolecules, for example. With reference to curve A (dashed line), afterbeing excited by a short or ultrashort optical pulse, a probabilityp_(A)(t) of a fluorescent emission from a first molecule may decay withtime, as depicted. In some cases, the decrease in the probability of aphoton being emitted over time can be represented by an exponentialdecay function p_(A)(t)=P_(Ao)*e^((−t/τ) ¹ ⁾, where P_(Ao) is an initialemission probability and τ₁ is a temporal parameter associated with thefirst fluorescent molecule that characterizes the emission decayprobability. τ₁ may be referred to as the “fluorescence lifetime,”“emission lifetime,” or “lifetime” of the first fluorescent molecule. Insome cases, the value of τ₁ can be altered by a local environment of thefluorescent molecule. Other fluorescent molecules can have differentemission characteristics than that shown in curve A. For example,another fluorescent molecule can have a decay profile that differs froma single exponential decay, and its lifetime can be characterized by ahalf-life value or some other metric.

A second fluorescent molecule may have a decay profile p_(B)(t) that isexponential, but has a measurably different lifetime τ₂, as depicted forcurve B in FIG. 5-7. The initial emission probability for curve B isshown in FIG. 5-7 as P_(Bo). In the example shown, the lifetime for thesecond fluorescent molecule of curve B is shorter than the lifetime forcurve A, and the probability of emission p_(B)(t) is higher sooner afterexcitation of the second molecule than for curve A. Differentfluorescent molecules can have lifetimes or half-life values rangingfrom about 0.1 ns to about 20 ns, in some embodiments.

Differences in fluorescent emission lifetimes can be used to discernbetween the presence or absence of different fluorescent moleculesand/or to discern between different environments or conditions to whicha fluorescent molecule is subjected. In some cases, discerningfluorescent molecules based on lifetime (rather than emissionwavelength, for example) can simplify aspects of an analyticalinstrument 5-100. As an example, wavelength-discriminating optics (suchas wavelength filters, dedicated detectors for each wavelength,dedicated pulsed optical sources at different wavelengths, and/ordiffractive optics) can be reduced in number or eliminated whendiscerning fluorescent molecules based on lifetime. In some cases, asingle pulsed optical source operating at a single characteristicwavelength can be used to excite different fluorescent molecules thatemit within a same wavelength region of the optical spectrum but havemeasurably different lifetimes. An analytic system that uses a singlepulsed optical source, rather than multiple sources operating atdifferent wavelengths, to excite and discern different fluorescentmolecules emitting in a same wavelength region can be less complex tooperate and maintain, more compact, and can be manufactured at lowercost.

Although analytic systems based on fluorescent lifetime analysis canhave certain benefits, the amount of information obtained by an analyticsystem and/or detection accuracy can be increased by allowing foradditional detection techniques. For example, some analytic systems5-160 can additionally be configured to discern one or more propertiesof a sample based on fluorescent wavelength and/or fluorescentintensity.

Referring again to FIG. 5-7, according to some embodiments, differentfluorescent lifetimes can be distinguished with a photodetector that isconfigured to time-bin fluorescent emission events following excitationof a fluorescent molecule. The time binning can occur during a singlecharge-accumulation cycle for the photodetector. A charge-accumulationcycle is an interval between read-out events during whichphoto-generated carriers are accumulated in bins of the time-binningphotodetector. The concept of determining fluorescent lifetime bytime-binning of emission events is introduced graphically in FIG. 5-8.At time te just prior to t₁, a fluorescent molecule or ensemble offluorescent molecules of a same type (e.g., the type corresponding tocurve B of FIG. 5-7) is (are) excited by a short or ultrashort opticalpulse. For a large ensemble of molecules, the intensity of emission canhave a time profile similar to curve B, as depicted in FIG. 5-8.

For a single molecule or a small number of molecules, however, theemission of fluorescent photons occurs according to the statistics ofcurve B in FIG. 5-7, for this example. A time-binning photodetector5-322 can accumulate carriers generated from emission events intodiscrete time bins. Three bins are indicated in FIG. 5-8, though fewerbins or more bins may be used in embodiments. The bins are temporallyresolved with respect to the excitation time te of the fluorescentmolecule(s). For example, a first bin can accumulate carriers producedduring an interval between times t₁ and t₂, occurring after theexcitation event at time t_(e). A second bin can accumulate carriersproduced during an interval between times t₂ and t₃, and a third bin canaccumulate carriers produced during an interval between times t₃ and t₄.When a large number of emission events are summed, carriers accumulatedin the time bins can approximate the decaying intensity curve shown inFIG. 5-8, and the binned signals can be used to distinguish betweendifferent fluorescent molecules or different environments in which afluorescent molecule is located.

Examples of a time-binning photodetector 5-322 are described in U.S.patent application Ser. No. 14/821,656, filed Aug. 7, 2015, titled“Integrated Device for Temporal Binning of Received Photons” and in U.S.patent application Ser. No. 15/852,571, filed Dec. 22, 2017, titled“Integrated Photodetector with Direct Binning Pixel,” which are bothincorporated herein by reference in their entirety. For explanationpurposes, a non-limiting embodiment of a time-binning photodetector isdepicted in FIG. 5-9. A single time-binning photodetector 5-322 cancomprise a photon-absorption/carrier-generation region 5-902, acarrier-discharge channel 5-906, and a plurality of carrier-storageregions 5-908 a, 5-908 b all formed on a semiconductor substrate.Carrier-transport channels 5-907 can connect between thephoton-absorption/carrier-generation region 5-902 and carrier-storageregions 5-908 a, 5-908 b. In the illustrated example, twocarrier-storage regions are shown, but there may be more or fewer. Therecan be a read-out channel 5-910 connected to the carrier-storageregions. The photon-absorption/carrier-generation region 5-902,carrier-discharge channel 5-906, carrier-storage regions 5-908 a, 5-908b, and read-out channel 5-910 can be formed by doping the semiconductorlocally and/or forming adjacent insulating regions to providephotodetection capability, confinement, and transport of carriers. Atime-binning photodetector 5-322 can also include a plurality ofelectrodes 5-920, 5-921, 5-922, 5-923, 5-924 formed on the substratethat are configured to generate electric fields in the device fortransporting carriers through the device. Other examples of suitablephotodetectors are described herein, including with a single chargestorage region and with multiple sequentially-coupled charge storageregions, but embodiments described herein are not so limited.

In operation, a portion of an excitation pulse 5-122 from a pulsedoptical source 5-106 (e.g., a mode-locked laser) is delivered to areaction chamber 5-330 over the time-binning photodetector 5-322.Initially, some excitation radiation photons 5-901 may arrive at thephoton-absorption/carrier-generation region 5-902 and produce carriers(shown as light-shaded circles). There can also be some fluorescentemission photons 5-903 that arrive with the excitation radiation photons5-901 and produce corresponding carriers (shown as dark-shaded circles).Initially, the number of carriers produced by the excitation radiationcan be too large compared to the number of carriers produced by thefluorescent emission. The initial carriers produced during a timeinterval t₀-t₁ can be rejected by gating them into a carrier-dischargechannel 5-906 with a first transfer gate 5-920, for example.

At a later times mostly fluorescent emission photons 5-903 arrive at thephoton-absorption/carrier-generation region 5-902 and produce carriers(indicated a dark-shaded circles) that provide useful and detectablesignal that is representative of fluorescent emission from the reactionchamber 5-330. According to some detection methods, a second electrode5-921 and third electrode 5-923 can be gated at a later time to directcarriers produced at a later time (e.g., during a second time intervalt₁-t₂) to a first carrier-storage region 5-908 a. Subsequently, a fourthelectrode 5-922 and fifth electrode 5-924 can be gated at a later time(e.g., during a third time interval t₂-t₃) to direct carriers to asecond carrier-storage region 5-908 b. Charge accumulation can continuein this manner after excitation pulses for a large number of excitationpulses to accumulate an appreciable number of carriers and signal levelin each carrier-storage region 5-908 a, 5-908 b. At a later time, thesignal can be read out from the bins. In some implementations, the timeintervals corresponding to each storage region are at the sub-nanosecondtime scale, though longer time scales can be used in some embodiments(e.g., in embodiments where fluorophores have longer decay times).

The process of generating and time-binning carriers after an excitationevent (e.g., excitation pulse from a pulsed optical source) can occuronce after a single excitation pulse or be repeated multiple times aftermultiple excitation pulses during a single charge-accumulation cycle forthe time-binning photodetector 5-322. After charge accumulation iscomplete, carriers can be read out of the storage regions via theread-out channel 5-910. For example, an appropriate biasing sequence canbe applied to electrodes 5-923, 5-924 and at least to electrode 5-940 toremove carriers from the storage regions 5-908 a, 5-908 b. The chargeaccumulation and read-out processes can occur in a massively paralleloperation on the optoelectronic chip 5-140 resulting in frames of data.

Although the described example in connection with FIG. 5-9 includesmultiple charge storage regions 5-908 a, 5-908 b in some cases a singlecharge storage region may be used instead. For example, only binl may bepresent in a time-binning photodetector 5-322. In such a case, a singlestorage regions 5-908 a can be operated in a variable time-gated mannerto look at different time intervals after different excitation events.For example, after pulses in a first series of excitation pulses,electrodes for the storage region 5-908 a can be gated to collectcarriers generated during a first time interval (e.g., during the secondtime interval t₁-t₂), and the accumulated signal can be read out after afirst predetermined number of pulses. After pulses in a subsequentseries of excitation pulses at the same reaction chamber, the sameelectrodes for the storage region 5-908 a can be gated to collectcarriers generated during a different interval (e.g., during the thirdtime interval t₂-t₃), and the accumulated signal can be read out after asecond predetermined number of pulses. Carriers could be collectedduring later time intervals in a similar manner if needed. In thismanner, signal levels corresponding to fluorescent emission duringdifferent time periods after arrival of an excitation pulse at areaction chamber can be produced using a single carrier-storage region.

In some embodiments, carriers produced during the second and third timeintervals may be collected and stored using sequentially-coupledcharge-carrier storage regions. For example, charge carriers producedduring the time interval t₁-t₂ may be collected in a first chargestorage region and transferred to a second charge storage region, andthen charge carriers produced during the time interval t₂-t₃ may becollected in the first charge storage region while the charge carrierscollected during time interval t₁-t₂ are read out to readout region FD.Alternatively or additionally, the charge carriers produced during timeinterval t₁-t₂ can be further transferred to and read out from a thirdcharge storage region, and then the charge carriers produced during timeinterval t₂-t₃ can be read out from the second charge storage region viathe third charge storage region (e.g., without resetting the voltage ofreadout region FD in between).

Regardless of how charge accumulation is carried out for different timeintervals after excitation, signals that are read out can provide ahistogram of bins that are representative of the fluorescent emissiondecay characteristics, for example. An example process is illustrated inFIG. 5-10A and FIG. 5-10B, for which two charge-storage regions are usedto acquire fluorescent emission from the reaction chambers. Thehistogram's bins can indicate a number of photons detected during eachtime interval after excitation of the fluorophore(s) in a reactionchamber 5-330. In some embodiments, signals for the bins will beaccumulated following a large number of excitation pulses, as depictedin FIG. 5-10A. The excitation pulses can occur at times t_(e1), t_(e2),t_(e3), . . . , teN which are separated by the pulse interval time T. Insome cases, there can be between 105 and 107 excitation pulses 5-122 (orportions thereof) applied to a reaction chamber during an accumulationof signals in the electron-storage regions for a single event beingobserved in the reaction chamber (e.g., a single nucleotideincorporation event in DNA analysis). In some embodiments, one bin (bin0) can be configured to detect an amplitude of excitation energydelivered with each optical pulse, and may be used as a reference signal(e.g., to normalize data). In other cases, the excitation pulseamplitude may be stable, determined one or more times during signalacquisition, and not determined after each excitation pulse so thatthere is no bin( )signal acquisition after each excitation pulse. Insuch cases, carriers produced by an excitation pulse can be rejected anddumped from the photon-absorption/carrier-generation region 5-902 asdescribed above in connection with FIG. 5-9.

In some implementations, only a single photon may be emitted from afluorophore following an excitation event, as depicted in FIG. 5-10A.After a first excitation event at time t_(e1), the emitted photon attime t_(f1) may occur within a first time interval (e.g., between timest₁ and t₂), so that the resulting electron signal is accumulated in thefirst electron-storage region (contributes to bin 1). In a subsequentexcitation event at time t_(e2), the emitted photon at time t_(f2) mayoccur within a second time interval (e.g., between times t₂ and t₃), sothat the resulting electron signal contributes to bin 2. After a nextexcitation event at time t_(e3), a photon may emit at a time t_(f3)occurring within the first time interval.

In some implementations, there may not be a fluorescent photon emittedand/or detected after each excitation pulse received at a reactionchamber 5-330. In some cases, there can be as few as one fluorescentphoton that is detected at a reaction chamber for every 10,000excitation pulses delivered to the reaction chamber. One advantage ofimplementing a mode-locked laser 5-113 as the pulsed excitation source5-106 is that a mode-locked laser can produce short optical pulseshaving high intensity and quick turn-off times at high pulse-repetitionrates (e.g., between 50 MHz and 250 MHz). With such highpulse-repetition rates, the number of excitation pulses within a 10millisecond charge-accumulation interval can be 50,000 to 250,000, sothat detectable signal can be accumulated.

After a large number of excitation events and carrier accumulations, thecarrier-storage regions of the time-binning photodetector 5-322 can beread out to provide a multi-valued signal (e.g., a histogram of two ormore values, an N-dimensional vector, etc.) for a reaction chamber. Thesignal values for each bin can depend upon the decay rate of thefluorophore. For example and referring again to FIG. 5-8, a fluorophorehaving a decay curve B will have a higher ratio of signal in bin 1 tobin 2 than a fluorophore having a decay curve A. The values from thebins can be analyzed and compared against calibration values, and/oreach other, to determine the particular fluorophore present. For asequencing application, identifying the fluorophore can determine thenucleotide or nucleotide analog that is being incorporated into agrowing strand of DNA, for example. For other applications, identifyingthe fluorophore can determine an identity of a molecule or specimen ofinterest, which may be linked to the fluorophore.

To further aid in understanding the signal analysis, the accumulated,multi-bin values can be plotted as a histogram, as depicted in FIG.5-10B for example, or can be recorded as a vector or location inN-dimensional space. Calibration runs can be performed separately toacquire calibration values for the multi-valued signals (e.g.,calibration histograms) for four different fluorophores linked to thefour nucleotides or nucleotide analogs. As an example, the calibrationhistograms may appear as depicted in FIG. 5-11A (fluorescent labelassociated with the T nucleotide), FIG. 5-11B (fluorescent labelassociated with the A nucleotide), FIG. 5-11C (fluorescent labelassociated with the C nucleotide), and FIG. 5-11D (fluorescent labelassociated with the G nucleotide). A comparison of the measuredmulti-valued signal (corresponding to the histogram of FIG. 5-10B) tothe calibration multi-valued signals can determine the identity “T”(FIG. 5-11A) of the nucleotide or nucleotide analog being incorporatedinto the growing strand of DNA.

In some implementations, fluorescent intensity can be used additionallyor alternatively to distinguish between different fluorophores. Forexample, some fluorophores may emit at significantly differentintensities or have a significant difference in their probabilities ofexcitation (e.g., at least a difference of about 35%) even though theirdecay rates may be similar. By referencing binned signals (bins 5-3) tomeasured excitation energy and/or other acquired signals, it can bepossible to distinguish different fluorophores based on intensitylevels.

In some embodiments, different numbers of fluorophores of the same typecan be linked to different nucleotides or nucleotide analogs, so thatthe nucleotides can be identified based on fluorophore intensity. Forexample, two fluorophores can be linked to a first nucleotide (e.g.,“C”) or nucleotide analog and four or more fluorophores can be linked toa second nucleotide (e.g., “T”) or nucleotide analog. Because of thedifferent numbers of fluorophores, there may be different excitation andfluorophore emission probabilities associated with the differentnucleotides. For example, there may be more emission events for the “T”nucleotide or nucleotide analog during a signal accumulation interval,so that the apparent intensity of the bins is significantly higher thanfor the “C” nucleotide or nucleotide analog.

Distinguishing nucleotides or any other biological or chemical specimensbased on fluorophore decay rates and/or fluorophore intensities enablesa simplification of the optical excitation and detection systems in ananalytical instrument 5-100. For example, optical excitation can beperformed with a single-wavelength source (e.g., a source producing onecharacteristic wavelength rather than multiple sources or a sourceoperating at multiple different characteristic wavelengths).Additionally, wavelength-discriminating optics and filters may not beneeded in the detection system to distinguish between fluorophores ofdifferent wavelengths. Also, a single photodetector can be used for eachreaction chamber to detect emission from different fluorophores.

The phrase “characteristic wavelength” or “wavelength” is used to referto a central or predominant wavelength within a limited bandwidth ofradiation (e.g., a central or peak wavelength within a 20 nm bandwidthoutput by a pulsed optical source). In some cases, “characteristicwavelength” or “wavelength” may be used to refer to a peak wavelengthwithin a total bandwidth of radiation output by a source.

Fluorophores having emission wavelengths in a range between about 560 nmand about 900 nm can provide adequate amounts of fluorescence to bedetected by a time-binning photodetector (which can be fabricated on asilicon wafer using CMOS processes). These fluorophores can be linked tobiological molecules of interest, such as nucleotides or nucleotideanalogs for genetic sequencing applications. Fluorescent emission inthis wavelength range can be detected with higher responsivity in asilicon-based photodetector than fluorescence at longer wavelengths.Additionally, fluorophores and associated linkers in this wavelengthrange may not interfere with incorporation of the nucleotides ornucleotide analogs into growing strands of DNA. In some implementations,fluorophores having emission wavelengths in a range between about 560 nmand about 660 nm can be optically excited with a single-wavelengthsource. An example fluorophore in this range is Alexa Fluor 647,available from Thermo Fisher Scientific Inc. of Waltham, Mass.Excitation energy at shorter wavelengths (e.g., between about 500 nm andabout 650 nm) may be used to excite fluorophores that emit atwavelengths between about 560 nm and about 900 nm. In some embodiments,the time-binning photodetectors can efficiently detect longer-wavelengthemission from the reaction chambers, e.g., by incorporating othermaterials, such as Ge, into the photodetectors' active regions.

VIII. Protein Sequencing Applications

Some aspects of the present disclosure may be useful for proteinsequencing. For example, some aspects of the present disclosure areuseful for determining amino acid sequence information from polypeptides(e.g., for sequencing one or more polypeptides). In some embodiments,amino acid sequence information can be determined for single polypeptidemolecules. In some embodiments, one or more amino acids of a polypeptideare labeled (e.g., directly or indirectly) and the relative positions ofthe labeled amino acids in the polypeptide are determined. In someembodiments, the relative positions of amino acids in a protein aredetermined using a series of amino acid labeling and cleavage steps.

In some embodiments, the identity of a terminal amino acid (e.g., anN-terminal or a C-terminal amino acid) is assessed, after which theterminal amino acid is removed and the identity of the next amino acidat the terminus is assessed, and this process is repeated until aplurality of successive amino acids in the polypeptide are assessed. Insome embodiments, assessing the identity of an amino acid comprisesdetermining the type of amino acid that is present. In some embodiments,determining the type of amino acid comprises determining the actualamino acid identity, for example by determining which of thenaturally-occurring 20 amino acids is the terminal amino acid (e.g.,using a recognition molecule that is specific for an individual terminalamino acid). However, in some embodiments assessing the identity of aterminal amino acid type can comprise determining a subset of potentialamino acids that can be present at the terminus of the polypeptide. Insome embodiments, this can be accomplished by determining that an aminoacid is not one or more specific amino acids (and therefore could be anyof the other amino acids). In some embodiments, this can be accomplishedby determining which of a specified subset of amino acids (e.g., basedon size, charge, hydrophobicity, binding properties) could be at theterminus of the polypeptide (e.g., using a recognition molecule thatbinds to a specified subset of two or more terminal amino acids).

Amino acids of a polypeptide can be indirectly labeled, for example,using amino acid recognition molecules that selectively bind one or moretypes of amino acids on the polypeptide. Amino acids of a polypeptidecan be directly labeled, for example, by selectively modifying one ormore types of amino acid side chains on the polypeptide with uniquelyidentifiable labels. Methods of selective labeling of amino acid sidechains and details relating to the preparation and analysis of labeledpolypeptides are known in the art (see, e.g., Swaminathan, et al. PLoSComput Biol. 2015, 11(2):e1004080). Accordingly, in some embodiments,the one or more types of amino acids are identified by detecting bindingof one or more amino acid recognition molecules that selectively bindthe one or more types of amino acids. In some embodiments, the one ormore types of amino acids are identified by detecting labeledpolypeptide.

In some embodiments, the relative position of labeled amino acids in aprotein can be determined without removing amino acids from the proteinbut by translocating a labeled protein through a pore (e.g., a proteinchannel) and detecting a signal (e.g., a Förster resonance energytransfer (FRET) signal) from the labeled amino acid(s) duringtranslocation through the pore in order to determine the relativeposition of the labeled amino acids in the protein molecule.

As used herein, sequencing a polypeptide refers to determining sequenceinformation for a polypeptide. In some embodiments, this can involvedetermining the identity of each sequential amino acid for a portion (orall) of the polypeptide. However, in some embodiments, this can involveassessing the identity of a subset of amino acids within the polypeptide(e.g., and determining the relative position of one or more amino acidtypes without determining the identity of each amino acid in thepolypeptide). However, in some embodiments amino acid contentinformation can be obtained from a polypeptide without directlydetermining the relative position of different types of amino acids inthe polypeptide. The amino acid content alone may be used to infer theidentity of the polypeptide that is present (e.g., by comparing theamino acid content to a database of polypeptide information anddetermining which polypeptide(s) have the same amino acid content).

In some embodiments, sequence information for a plurality of polypeptideproducts obtained from a longer polypeptide or protein (e.g., viaenzymatic and/or chemical cleavage) can be analyzed to reconstruct orinfer the sequence of the longer polypeptide or protein. Accordingly,some embodiments provide compositions and methods for sequencing apolypeptide by sequencing a plurality of fragments of the polypeptide.In some embodiments, sequencing a polypeptide comprises combiningsequence information for a plurality of polypeptide fragments toidentify and/or determine a sequence for the polypeptide. In someembodiments, combining sequence information may be performed by computerhardware and software. The methods described herein may allow for a setof related polypeptides, such as an entire proteome of an organism, tobe sequenced. In some embodiments, a plurality of single moleculesequencing reactions may be performed in parallel (e.g., on a singlechip). For example, in some embodiments, a plurality of single moleculesequencing reactions are each performed in separate sample wells on asingle chip.

In some embodiments, methods provided herein may be used for thesequencing and identification of an individual protein in a samplecomprising a complex mixture of proteins. Some embodiments providemethods of uniquely identifying an individual protein in a complexmixture of proteins. In some embodiments, an individual protein isdetected in a mixed sample by determining a partial amino acid sequenceof the protein. In some embodiments, the partial amino acid sequence ofthe protein is within a contiguous stretch of approximately 5 to 50amino acids.

Without wishing to be bound by any particular theory, it is believedthat most human proteins can be identified using incomplete sequenceinformation with reference to proteomic databases. For example, simplemodeling of the human proteome has shown that approximately 98% ofproteins can be uniquely identified by detecting just four types ofamino acids within a stretch of 6 to 40 amino acids (see, e.g.,Swaminathan, et al. PLoS Comput Biol. 2015, 11(2):e1004080; and Yao, etal. Phys. Biol. 2015, 12(5):055003). Therefore, a complex mixture ofproteins can be degraded (e.g., chemically degraded, enzymaticallydegraded) into short polypeptide fragments of approximately 6 to 40amino acids, and sequencing of this polypeptide library would reveal theidentity and abundance of each of the proteins present in the originalcomplex mixture. Compositions and methods for selective amino acidlabeling and identifying polypeptides by determining partial sequenceinformation are described in in detail in U.S. patent application Ser.No. 15/510,962, filed Sep. 15, 2015, titled “SINGLE MOLECULE PEPTIDESEQUENCING,” which is incorporated by reference in its entirety.

Sequencing in accordance with some embodiments can involve immobilizinga polypeptide on a surface of a substrate or solid support, such as achip or integrated device. In some embodiments, a polypeptide can beimmobilized on a surface of a sample well (e.g., on a bottom surface ofa sample well) on a substrate. In some embodiments, a first terminus ofa polypeptide is immobilized to a surface, and the other terminus issubjected to a sequencing reaction as described herein. For example, insome embodiments, a polypeptide is immobilized to a surface through aC-terminal end, and terminal amino acid recognition and degradationproceeds from an N-terminal end of the polypeptide toward the C-terminalend. In some embodiments, the N-terminal amino acid of the polypeptideis immobilized (e.g., attached to the surface). In some embodiments, theC-terminal amino acid of the polypeptide is immobilized (e.g., attachedto the surface). In some embodiments, one or more non-terminal aminoacids are immobilized (e.g., attached to the surface). The immobilizedamino acid(s) can be attached using any suitable covalent ornon-covalent linkage, for example as described herein. In someembodiments, a plurality of polypeptides are attached to a plurality ofsample wells (e.g., with one polypeptide attached to a surface, forexample a bottom surface, of each sample well), for example in an arrayof sample wells on a substrate.

Some aspects of the present disclosure provide a method of sequencing apolypeptide by detecting luminescence of a labeled polypeptide which issubjected to repeated cycles of terminal amino acid modification andcleavage. For example, FIG. 5-12 shows a method of sequencing a labeledpolypeptide by Edman degradation in accordance with some embodiments. Insome embodiments, the method generally proceeds as described herein forother methods of sequencing by Edman degradation. For example, in someembodiments, steps (1) and (2) shown in FIG. 5-12 may be performed asdescribed elsewhere herein for terminal amino acid modification andterminal amino acid cleavage, respectively, in an Edman degradationreaction.

As shown in the example depicted in FIG. 5-12, in some embodiments, themethod comprises a step of (1) modifying the terminal amino acid of alabeled polypeptide. As described elsewhere herein, in some embodiments,modifying comprises contacting the terminal amino acid with anisothiocyanate (e.g., PITC) to form an isothiocyanate-modified terminalamino acid. In some embodiments, an isothiocyanate modification 5-1210converts the terminal amino acid to a form that is more susceptible toremoval by a cleaving reagent (e.g., a chemical or enzymatic cleavingreagent, as described herein). Accordingly, in some embodiments, themethod comprises a step of (2) removing the modified terminal amino acidusing chemical or enzymatic means detailed elsewhere herein for Edmandegradation.

In some embodiments, the method comprises repeating steps (1) through(2) for a plurality of cycles, during which luminescence of the labeledpolypeptide is detected, and cleavage events corresponding to theremoval of a labeled amino acid from the terminus may be detected as adecrease in detected signal. In some embodiments, no change in signalfollowing step (2) as shown in FIG. 5-12 identifies an amino acid ofunknown type. Accordingly, in some embodiments, partial sequenceinformation may be determined by evaluating a signal detected followingstep (2) during each sequential round by assigning an amino acid type bya determined identity based on a change in detected signal oridentifying an amino acid type as unknown based on no change in adetected signal.

Some aspects of the present disclosure provide methods of polypeptidesequencing in real-time by evaluating binding interactions of terminalamino acids with labeled amino acid recognition molecules and a labeledcleaving reagent (e.g., a labeled exopeptidase). FIG. 5-13 shows anexample of a method of sequencing in which discrete binding events giverise to signal pulses of a signal output 5-1300. The inset panel of FIG.5-13 illustrates a general scheme of real-time sequencing by thisapproach. As shown, a labeled amino acid recognition molecule 5-1310selectively binds to and dissociates from a terminal amino acid (shownhere as lysine), which gives rise to a series of pulses in signal output5-1300 which may be used to identify the terminal amino acid. In someembodiments, the series of pulses provide a pulsing pattern which may bediagnostic of the identity of the corresponding terminal amino acid.

Without wishing to be bound by theory, labeled amino acid recognitionmolecule 5-1310 selectively binds according to a binding affinity (KD)defined by an association rate of binding (kon) and a dissociation rateof binding (koff). The rate constants koff and kon are the criticaldeterminants of pulse duration (e.g., the time corresponding to adetectable binding event) and interpulse duration (e.g., the timebetween detectable binding events), respectively. In some embodiments,these rates can be engineered to achieve pulse durations and pulse ratesthat give the best sequencing accuracy.

As shown in the inset panel, a sequencing reaction mixture furthercomprises a labeled cleaving reagent 5-1320 comprising a detectablelabel that is different than that of labeled amino acid recognitionmolecule 5-1310. In some embodiments, labeled cleaving reagent 5-1320 ispresent in the mixture at a concentration that is less than that oflabeled amino acid recognition molecule 5-1310. In some embodiments,labeled cleaving reagent 5-1320 displays broad specificity such that itcleaves most or all types of terminal amino acids.

As illustrated by the progress of signal output 5-1300, in someembodiments, terminal amino acid cleavage by labeled cleaving reagent5-1320 gives rise to a uniquely identifiable signal pulse, and theseevents occur with lower frequency than the binding pulses of a labeledamino acid recognition molecule 5-1310. In this way, amino acids of apolypeptide can be counted and/or identified in a real-time sequencingprocess. As further illustrated in signal output 5-1300, in someembodiments, a labeled amino acid recognition molecule 5-1310 isengineered to bind more than one type of amino acid with differentbinding properties corresponding to each type, which produces uniquelyidentifiable pulsing patterns. In some embodiments, a plurality oflabeled amino acid recognition molecules may be used, each with adiagnostic pulsing pattern which may be used to identify a correspondingterminal amino acid.

IX. Conclusion

Having thus described several aspects and embodiments of the technologyof the present disclosure, it is to be appreciated that variousalterations, modifications, and improvements will readily occur to thoseof ordinary skill in the art. Such alterations, modifications, andimprovements are intended to be within the spirit and scope of thetechnology described herein. It is, therefore, to be understood that theforegoing embodiments are presented by way of example only and that,within the scope of the appended claims and equivalents thereto,inventive embodiments may be practiced otherwise than as specificallydescribed. In addition, any combination of two or more features,systems, articles, materials, kits, and/or methods described herein, ifsuch features, systems, articles, materials, kits, and/or methods arenot mutually inconsistent, is included within the scope of the presentdisclosure.

Also, as described, some aspects may be embodied as one or more methods.The acts performed as part of the method may be ordered in any suitableway. Accordingly, embodiments may be constructed in which acts areperformed in an order different than illustrated, which may includeperforming some acts simultaneously, even though shown as sequentialacts in illustrative embodiments.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. The transitional phrases “consisting of” and “consisting essentiallyof” shall be closed or semi-closed transitional phrases, respectively.

What is claimed is:
 1. An integrated circuit, comprising: aphotodetection region configured to: receive, in a first direction,incident photons; generate, in response to receiving the incidentphotons, charge carriers; and induce, in the first direction, a firstintrinsic electric field; and one or more charge storage regionsconfigured to receive the charge carriers from the photodetectionregion.
 2. The integrated circuit of claim 1, wherein the photodetectionregion comprises a first layer having a first intrinsic electricpotential level and a second layer positioned, in the first direction,after the first layer and having a second intrinsic electric potentiallevel that is different from the first intrinsic electric potentiallevel.
 3. The integrated circuit of claim 2, wherein the first layer hasa first dopant concentration and the second layer has a second dopantconcentration that is higher than the first dopant concentration.
 4. Theintegrated circuit of claim 3, wherein the photodetection region furthercomprises a third layer positioned, in the first direction, after thesecond layer and having a third dopant concentration that is higher thanthe second dopant concentration.
 5. The integrated circuit of claim 1,wherein the photodetection region comprises a mask having a triangularopening, with a base of the triangular opening positioned, in a seconddirection, after an apex of the triangular opening, the mask configuredto induce, in the second direction, a second intrinsic electric fieldfrom the photodetection region to the one or more charge storageregions.
 6. The integrated circuit of claim 1, wherein thephotodetection region has a first dopant concentration and the one ormore charge storage regions have at least a second dopant concentrationthat is higher than the first dopant concentration.
 7. The integratedcircuit of any one of claim 1, further comprising one or more transfergates configured to control transfer of charge carriers from thephotodetection region to the one or more charge storage regions and/orfrom the one or more charge storage regions to a readout region, whereinthe one or more transfer gates are positioned, in the first direction,after the photodetection region and the one or more charge storageregions.
 8. An integrated circuit, comprising: a photodetection regionconfigured to: generate, in response to receiving incident photons,charge carriers; and induce, in a first direction, a first intrinsicelectric field; one or more charge storage regions configured to receivethe charge carriers from the photodetection region; and one or moretransfer gates positioned, in the first direction, after thephotodetection region and the one or more charge storage regions, andconfigured to control transfer of charge carriers from thephotodetection region to the one or more charge storage regions and/orfrom the one or more charge storage regions to a readout region.
 9. Theintegrated circuit of claim 8, wherein the photodetection regioncomprises a first layer having a first intrinsic electric potentiallevel and a second layer positioned, in the first direction, after thefirst layer and having a second intrinsic electric potential level thatis different from the first intrinsic electric potential level.
 10. Theintegrated circuit of claim 9, wherein the first layer has a firstdopant concentration and the second layer has a second dopantconcentration that is higher than the first dopant concentration. 11.The integrated circuit of claim 10, wherein the photodetection regionfurther comprises a third layer positioned, in the first direction,after the second layer and having a third dopant concentration that ishigher than the second dopant concentration.
 12. The integrated circuitof claim 8, wherein the photodetection region comprises a mask having atriangular opening, with a base of the triangular opening positioned, ina second direction, after an apex of the triangular opening, the maskconfigured to induce, in the second direction, a second intrinsicelectric field from the photodetection region to the one or more chargestorage regions.
 13. The integrated circuit of claim 8, wherein thephotodetection region has a first intrinsic electric potential level andthe one or more charge storage regions have at least a second intrinsicelectric potential level that is different from the first intrinsicelectric potential level.
 14. The integrated circuit of claim 13,wherein the photodetection region has a first dopant concentration andthe one or more charge storage regions have at least a second dopantconcentration that is higher than the first dopant concentration.
 15. Amethod, comprising: inducing, in a first direction, a first intrinsicelectric field in a photodetection region of an integrated circuit;generating, in the photodetection region in response to receivingincident photons, charge carriers; receiving, at one or more chargestorage regions, the charge carriers generated from the photodetectionregion; and controlling transfer of charge carriers from thephotodetection region to the one or more charge storage regions and/orfrom the one or more charge storage regions to a readout region usingone or more transfer gates positioned, in the first direction, after thephotodetection region and the one or more charge storage regions. 16.The method of claim 15, wherein the first intrinsic electric field isinduced, at least in part, by a first layer of the photodetection regionhaving a first intrinsic electric potential level and a second layer ofthe photodetection region positioned, in the first direction, after thefirst layer and having a second intrinsic electric potential level thatis different from the first intrinsic electric potential level.
 17. Themethod of claim 16, wherein the first intrinsic electric field isinduced, at least in part, by a first dopant concentration of the firstlayer and a second dopant concentration of the second layer that ishigher than the first dopant concentration.
 18. The method of claim 17,wherein the first intrinsic electric field is induced, at least in part,by a third layer of the photodetection region that is positioned, in thefirst direction, after the second layer and has a third dopantconcentration that is higher than the second dopant concentration. 19.The method of claim 15, further comprising: inducing, in a seconddirection, a second intrinsic electric field from the photodetectionregion to the one or more charge storage regions, wherein the secondintrinsic electric field is induced, at least in part, by a mask of thephotodetection region, the mask having a triangular opening with a baseof the triangular opening positioned, in the second direction, after anapex of the triangular opening.
 20. The method of claim 15, furthercomprising: inducing in a second direction, a second intrinsic electricfield from the photodetection region to the one or more charge storageregions, wherein the second intrinsic electric field is induced, atleast in part, by a first dopant concentration of the photodetectionregion and at least a second dopant concentration of the one or morecharge storage regions that is higher than the first dopantconcentration.